Controlled/modified release oral methylphenidate formulations

ABSTRACT

The invention is directed to oral modified/controlled release methylphenidate formulations which provide a rapid initial onset of effect and a prolonged duration of effect. Preferably, the peak concentration is lower than that provided by the reference standard for immediate release methylphenidate formulations, and the duration of effect falls rapidly at the end of the dosing interval so as not to affect the appetite of the patient at dinner nor the patient&#39;s sleep thereafter.

[0001] This application claims priority from U.S. ProvisionalApplication No. 60/112,667, filed Dec. 17, 1998, the disclosure of whichis hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Sustained release dosage forms are central in the search forimproved therapy, both through improved patient compliance and decreasedincidences of adverse drug reactions. It is the intent of all sustainedrelease formulations to provide a longer period of pharmacologic actionafter administration than is ordinarily obtained after administration ofimmediate-release dosage forms. Sustained release compositions may beused to delay absorption of a medicament until it has reached certainportions of the alimentary tract, and maintain a desired concentrationof said medicament in the blood stream for a longer duration than wouldoccur if conventional rapid release dosage forms are administered. Suchlonger periods of response provide for many therapeutic benefits thatare not achieved with corresponding short acting, immediate releasepreparations. Thus, therapy may be continued without interrupting thesleep of the patient, which is of special importance, for example, whentreating a patient for moderate to severe pain (e.g., a post-surgerypatient, a cancer patient, etc.), or for those patients who experiencemigraine headaches on awakening, as well as for the debilitated patientfor whom sleep is essential. A further general advantage of longeracting drug preparations is improved patient compliance resulting fromthe avoidance of missed doses through patient forgetfulness.

[0003] Unless conventional rapid acting drug therapy is carefullyadministered at frequent intervals to maintain effective steady stateblood levels of the drug, peaks and valleys in the blood level of theactive drug occurs because of the rapid absorption, systemic excretionof the compound and through metabolic inactivation, thereby producingspecial problems in maintenance therapy of the patient. In view of this,it is considered a goal of many skilled in the art that a controlledrelease dosage form will ideally provide therapeutic concentration ofthe drug in blood that is maintained throughout the dosing interval witha reduction in the peak/trough concentration ratio. Central to thedevelopment process are the many variables that influence the in vivorelease and subsequent absorption of the active ingredients from thegastrointestinal tract.

[0004] It is known in the pharmaceutical art to prepare compositionswhich provide for sustained release of pharmacologically activesubstances contained in the compositions after oral administration tohumans and animals. Sustained release formulations known in the artinclude specially coated pellets, coated tablets and capsules, and ionexchange resins, wherein the slow release of the active medicament isbrought about through selective breakdown of the coating of thepreparation or through compounding with a special matrix to affect therelease of a drug. Some sustained release formulations provide forrelated sequential release of a single dose of an active compound atpredetermined periods after administration.

[0005] While controlled and/or sustained release compositions haveconstituted a definite advance in the art, improvements in thesecompositions have been sought, particularly for preparations availablefor conditions such as Attention Deficit Hyperactivity Disorder (ADHD),diabetes etc.

[0006] Attention Deficit Disorders are the most common psychiatricdisorders in children (Campbell et al. 1992) with reported rates rangingfrom 4% to 9% (Aman et al. 1983). Attention Deficit Disorder (ADD) ischaracterized by inattention and impulsivity and may be present withhyperactivity (ADHD) (Shaywitz et al. 1984). Other characteristics mayinclude aggressiveness, stealing, lying, truancy, setting fires, runningaway, explosiveness, cognitive and learning problems as well as poorsocial skills (Campbell et al. 1992). It is four to five times morefrequent in boys than girls (Campbell et al. 1992).

[0007] Stimulant medication, such as amphetamines, have been shown to bethe most effective agents in the treatment of children with disorders ofactivity modulation and attention regulation and result in significantimprovement in 70 to 80 percent of affected children (Shaywitz et al.1984). Positive effects of stimulants have been documented in a varietyof areas including behavioral, social, perceptual performance, motoractivity, impulse control, attention regulation and cognitiveperformance (Barkley 1977, Kavale 1983, Offenbacher et al. 1983,Rosenthal et al 1978).

[0008] Methylphenidate {dl-threo-methyl-2-phenyl-2-(2-piperidyl)acetate} is the psychostimulant used most frequently in the treatment ofhyperactivity and attention deficit disorder. It appears to have ahigher incidence of positive effects and a lower incidence of adverseeffects than other psychostimulants. The efficacy of methylphenidate(“MPH”) in improving attention and behavioral symptoms has beensupported by many studies.

[0009] Immediate release methylphenidate preparations, because of theirshort half-life, require frequent administration at short intervals toensure adequate treatment throughout a child's school day. The rapidonset and offset of immediate release methylphenidate preparations meansthat a medicated child with attention deficit disorder will be maximallyaffected only for relatively brief periods during the day. Due to itsshort half-life, MPH is usually given twice per day, usually once afterbreakfast and once during the school day, an event that some childrenand some school personnel apparently avoid, resulting in poor compliancewith prescribed regimens (Brown et al., 1985; Firestone 1982).Compliance is a major problem for children who require a midday ormidafternoon dose as many schools prohibit children from takingmedications during the school day and others often insist that allmedications be given by a nurse. Poor compliance in taking medicationmay explain, in part, the variable and conflicting results reported inmany studies of the effect of medication on improving the behavior ofhyperactive children. These limitations of immediate releasemethylphenidate led to interest in products with longer effectiveperiods of action. These limitations of immediate releasemethylphenidate preparations led to interest in products with longereffective periods of action.

[0010] A sustained release form of methylphenidate (Ritalin® SR) iscommercially available. As a result of many clinical trials, variousopinion leaders in treatment of attention deficit hyperactivity disorderhave made the following comments regarding Ritalin® SR (sustainedrelease methylphenidate) produced by Ciba-Geigy: (i) Ritalin® SR doesnot have a sufficiently early onset of effect to allow for behavioralmanagement in the early morning; (ii) Ritalin® SR does not have thebeneficial late effects that would be produced by a lunch time dose ofimmediate release methylphenidate, thus defeating the purpose of usingan SR formulation; (iii) The effects of Ritalin® SR are inconsistent orerratic over the course of the day.

[0011] There is a need in the art to develop drug formulations whichprovide a rapid onset, a prolonged action, followed by rapid offset ofeffect in order to overcome the deficiencies of the current state of theart.

OBJECTS AND SUMMARY OF THE INVENTION

[0012] It is an object of the present invention to provide new oraldosage formulations of methylphenidate or similarly acting drugs whichresults in improved patient compliance.

[0013] It is an object of the present invention to provide new oraldosage formulations which represent improvements over currentlyavailable preparations available for conditions such as AttentionDeficit Hyperactivity Disorder (ADHD).

[0014] It is an object of the present invention to provide new oraldosage formulations of methylphenidate or similarly acting drugs whichensure adequate treatment throughout a child's school day.

[0015] It is an object of the present invention to provide new oraldosage formulations which allow a child with attention deficit disorderto be maximally treated throughout the daytime, while being administeredonly once, i.e., in the morning.

[0016] It is a further object of the present invention to provide newcontrolled/modified release oral dosage formulations which provide arapid onset and rapid offset with an extended release of activemedicaments incorporated therein.

[0017] It is yet another object of the present invention to provide newcontrolled/modified release oral dosage formulations which are useful inall types of pharmaceutically active ingredients and which can extendthe time of release of all such ingredients.

[0018] It is yet another object of the present invention to provide anoral controlled release formulation which combines both a rapid onsetand sustained plasma concentrations throughout the day.

[0019] It is yet another object of the present invention to provide a“multi-layer release” (MLR) technology which is useful for all types ofpharmaceutically active ingredients and which can extend the duration ofaction for a desired length of time.

[0020] To address the above-mentioned deficiencies as well as othergoals, the present invention is directed in part to a controlled releaseproduct which is intended to combined both a rapid onset and sustainedplasma concentrations throughout the day. Significantly, theformulations of the present invention provide a rapid onset, a prolongedaction, followed by rapid offset of effect, i.e., a “square wave”profile.

[0021] In accordance with the above objects and others, the presentinvention is directed in part to an oral dosage form comprising aneffective amount of methylphenidate or a pharmaceutically acceptablesalt thereof and at least one release modifying material which causesthe formulation to provide a time to maximum plasma concentration atabout 0.5 to about 4 hours after oral administration, a peak plasmaconcentration from about 3 ng/ml to about 6.5 ng/ml per 20 mg dose ofmethylphenidate contained in the oral dosage form, wherein the peakplasma concentration is from about 1.0 to about 2.0 times the plasmaconcentration of methylphenidate provided by the formulation at about 9hours after oral administration, and wherein the duration of effectprovided by the methylphenidate contained in the formulation falls beloweffective plasma concentrations at about 8 to about 12 hours after oraladministration. In certain preferred embodiments, the oral dosage formprovides a time to maximum plasma concentration at about 0.5 to about 2hours after oral administration. In certain further preferredembodiments, the peak plasma concentration is from about 1.0 to about1.7 times the plasma concentration of methylphenidate provided by theoral dosage form at about 9 hours after oral administration. In certainfurther preferred embodiments, the duration of effect provided by themethylphenidate contained in the oral dosage form falls below effectiveplasma concentrations at about 8 to about 10 hours after oraladministration.

[0022] In certain further preferred embodiments, the formulationprovides a time to maximum plasma concentration at about 0.5 to about 4hours after oral administration and provides effective blood levels forat least about 6 hours after administration.

[0023] In certain further preferred embodiments, the formulationexhibits a “plateau” in the blood plasma curve which lasts from about 2hours to about 6 hours. Other embodiments exhibit a “plateau” whichlasts from about 6 hours to about 12 hours. The “plateau” ischaracterized by a stabilized plasma concentration, wherein the plasmalevel at the end of the measured interval does not differ by more than20%, preferably by no more than 10% of the plasma concentration at thebeginning of the measured interval.

[0024] In certain further preferred embodiments, the formulationexhibits a bimodal release of active agent from the dosage form. Bimodalrelease of the active agent is characterized by the active agent beingrelease from the dosage form by more than one distinct release rate. Insome embodiments, the release rates can be separated by a no-release ora substantially no-release interval, although this is not alwaysnecessary.

[0025] In certain further preferred embodiments, the formulationexhibits a biphasic absorption of the active agent. Biphasic absorptionof the active agent is characterized by the active agent being absorbedthrough a natural barrier (e.g. the mucosal lining of thegastrointestinal tract) by more than one distinct absorption rate. Insome embodiments, the absorption rates can be separated by ano-absorption or a substantially no-absorption interval, although thisis not always necessary. A formulation can exhibit both biphasicabsorption and bimodal release of the active agent, with the biphasicabsorption being a function of the bimodal release rate. However,biphasic absorption is not always attributed to release rate and canoccur in a formulation not exhibiting bimodal release.

[0026] In preferred embodiments the formulation exhibits bimodal releaseand/or biphasic absorption to provide a “plateau” in the blood plasmacurve which lasts from about 2 hours to about 6 hours. Other embodimentsexhibit bimodal release and/or biphasic absorption to provide a“plateau” which lasts from about 6 hours to about 12 hours. Otherembodiments, maintain effective plasma levels of the active agent forabout 16 to about 18 hours after administration of the dosage form.

[0027] The present invention is further directed to an oral dosage formcomprising an effective amount of methylphenidate or a pharmaceuticallyacceptable salt thereof and at least one release modifying materialwhich causes the formulation to provide a in-vitro dissolution of thedrug of from about 0 to about 45% released after 0.25 hour; from about10 to about 50% released after about 1 hour; from about 30 to about 80%drug released after about 4 hours; not less than about 65% drug releasedafter 8 hours; and not less than about 80% of the drug released afterabout 12 hours; the oral dosage form when orally administered to a humanpatient further providing a time to maximum plasma concentration atabout 0.5 to about 2 hours after oral administration, and a duration ofeffect which lasts from about 8 to about 10 hours after oraladministration, wherein the plasma concentration of the drug rapidlyfalls at about 8 to about 10 hours after oral administration to a levelwhich is below the minimum effective plasma concentration. In certainpreferred embodiments, the oral dosage form, when orally administered toa human patient, provides a peak plasma concentration from about 4 ng/mlto about 6.5 ng/ml per 20 mg dose of methylphenidate contained in theoral dosage form. In certain preferred embodiments, the oral dosageform, when orally administered, provides a peak plasma concentrationfrom about 5 ng/ml to about 6.5 ng/ml per 20 mg dose of methylphenidatecontained in the oral dosage form. In certain further preferredembodiments, the oral dosage form provides peak plasma concentrationfrom about 1.0 to about 2.0 times the plasma concentration ofmethylphenidate provided by the formulation at about 9 hours after oraladministration, and more preferably from about 1.0 to about 1.7 timesthe plasma concentration of methylphenidate provided by the formulationat about 9 hours after oral administration.

[0028] With respect to the drug methylphenidate and ADHD, the benefitsof the new formulations described herein include: a) the ability toobviate the need for a lunch-time dose at school and b) an onset of drugeffect which is equivalent to that of an immediate releasemethylphenidate formulation; and c) the duration of action extendingbeyond the school day, i.e., a duration of effective blood levels of10-12 hours.

[0029] In certain embodiments of the invention, the controlled/modifiedrelease formulation is based on a multi-layered release (“MLR”)technology, and the drug product can be in an oral capsule containingbeads. In the case of beads, encapsulated in a capsule, each beadcontains a series of layers with different characteristics—an outerimmediate release layer, a release delaying layer (enteric coat), acontrolled release layer over an immediate release layer. The MLRformulation is designed such that upon oral administration, theformulation provides a rapid dissolution and absorption of the outerlayer of the formulation which contains a portion of the drug inimmediate release form, thereby resulting in a rapid rise of the drug totherapeutic plasma levels. This is followed by a period of no absorption(due to an enteric coating), followed thereafter by a controlled releaseof the drug from the formulation to maintain plasma levels. Afterabsorption of the drug from an immediate release core, plasma levelsthen rapidly decrease. By virtue of the release of the drug from the MLRformulation, the plasma level of the drug, when plotted on atime/concentration curve, takes the appearance of a “square wave”.

[0030] In certain preferred embodiments, an acrylic resin is utilized toprovide the controlled slow release of therapeutically activeingredients over a predetermined or a specified period of time, theacrylic resin thereby comprising a significant part of the “basecomposition”. Base compositions prepared from such acrylic resinsprovide sustained release of therapeutically active ingredients over aperiod of time from five hours and for as much as 24 hours afteradministration, generally oral administration, in humans or animals.

[0031] In other embodiments of the invention, the formulations of theinvention are composed of:

[0032] (i) a mixture of immediate release particles (e.g., beads) andenteric coated immediate release particles (e.g., beads); (ii) a mixtureof immediate release particles (e.g., beads) and enteric coatedcontrolled release particles (e.g., beads) or (iii) a mixture ofimmediate release particles (e.g., beads) and controlled releaseparticles (e.g., beads). In each such instance, the mixture of particlespossessing different release properties are blended together and filledinto hard gelatin capsules.

[0033] In certain preferred embodiments, the controlled/modified releasemethylphenidate formulations of the invention consist of a plurality ofsingle beads, each containing an immediate-release component incombination with an enteric coated controlled-release component toproduce a delay in the absorption process. The drug product is an oralcapsule containing methylphenidate beads. Each bead contains a series oflayers with different release characteristics—an outer immediate releaselayer; a release delaying layer; a controlled release layer; and animmediate release core. The final product is a capsule containingmulti-layer release (MLR) beads which have both immediate release andcontrolled release components. It is made up of a controlled releasebead which is enteric coated to delay dissolution until after gastricemptying. The enteric coated controlled release bead has an immediaterelease topcoat to provide an initial rate of absorption equal to orgreater than Ritalin immediate release tablets. The immediate releasecomponent represents 40% of the total dose per bead and the controlledrelease component represents 60%. This formulation is designed toproduce a rapid rise to therapeutic plasma levels after oraladministration, due to the rapid-dissolution and absorption of the outerlayer, followed by a period of reduced absorption and then controlledrelease of the immediate release core, to maintain therapeutic plasmalevels. After absorption of the immediate release core, plasma levelswould then rapidly decrease according to the elimination kinetics ofmethylphenidate. The results of a bioavailability study of thisformulation indicate a biphasic release profile that is consistent withthe pharmaceutical rationale discussed herein.

[0034] In other embodiments of the invention, the bead size of theformulations can be adjusted in order to obtain a desiredpharmacokinetic profile based on the correlation between gastricemptying and bead size. A smaller bead size exhibits faster gastricemptying as compared to a larger bead size.

[0035] Other objects and advantages of the present invention will beapparent from the further reading of the specification and of theappended claims.

[0036] The term “pH-dependent” for purposes of the present invention isdefined as having characteristics (e.g. dissolution) which varyaccording to environmental pH (e.g., due to changes in the in-vitrodissolution media, or due to passage of the dosage form through thegastrointestinal tract.

[0037] The term “pH-independent” for purposes of the present inventionis defined as having characteristics (e.g., dissolution) which aresubstantially unaffected by pH, in that a difference, at any given time,between an amount of methylphenidate released at one pH and an amountreleased at any other pH, when measured in-vitro using the USP PaddleMethod of U.S. Pharmacopeia XXII (1990) at 100 rpm in 900 ml aqueousbuffer, is no greater than 10%.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The following drawings are illustrative of embodiments of theinvention and are not meant to limit the scope of the invention asencompassed by the claims.

[0039]FIG. 1 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulation 1 andRitalin® as a function of time when given under fasting conditions.

[0040]FIG. 2 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulation 1 andRitalin® as a function of time when given under fed conditions.

[0041]FIG. 3 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulation 1 asa function of time when given under fasting and fed conditions.

[0042]FIG. 4 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Ritalin® as afunction of time when given under fasting and fed conditions.

[0043]FIG. 5 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulation 2under fasting and fed conditions, and Ritalin® SR under fastingconditions, as a function of time.

[0044]FIG. 6 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulation 3under fasting and fed conditions, and Ritalin® SR under fastingconditions, as a function of time.

[0045]FIG. 7 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulations 2and 3 under fasting conditions as a function of time.

[0046]FIG. 8 is a graphical comparison of the mean plasma concentrationof methylphenidate when test subjects are treated with Formulations 2and 3 under fed conditions as a function of time.

[0047]FIG. 9 a graphical representation of one target plasma drugconcentration profile in accordance with the invention.

[0048]FIG. 10 is a graphical representation of the correlation of thein-vitro drug dissolution profile with the in-vivo absorption profile ofFormulation 1.

[0049]FIG. 11 is a graphical representation of a target absorptionprofile of a formulation in accordance with the invention.

DETAILED DESCRIPTION

[0050] Methylphenidate (2-Piperidineacetic acid, α-phenyl-, methylester) is a piperidine derivative that is structurally related toamphetamine, and is commercially available in the form of thehydrochloride salt. Methylphenidate is the psychostimulant used mostfrequently in the treatment of hyperactivity and attention deficitdisorder. It appears to have a higher incidence of positive effects anda lower incidence of adverse effects than other psychostimulants. Thecontrolled/modified release methylphenidate formulations of theinvention are thought to act by increasing extracellular dopamine andnorepinephrine with the presumed mechanism of action being uptake blockat the nerve terminal transporters.

[0051] The pharmacological properties of methylphenidate are essentiallythe same as the amphetamines. However, in contrast to amphetamines,methylphenidate is a mild CNS stimulant with more prominent effects onmental than motor activities. Methylphenidate contains erythro and threoisomers. Locomotor stimulant action is specific to stereo-structure,whereas monoamine oxidase inhibition is not. It has been speculated thatthe mechanism of locomotor stimulant action of methylphenidate may beother than the inhibition of monoamine oxidase. Studies suggest thatsynaptic inhibition of catecholamine uptake by d-threo methylphenidatemay be involved fundamentally in behavioral and pressor effects of theracemic drug. Methylphenidate promotes a dose-dependent behavioralprofile that is very comparable to that of amphetamine. Amphetamineincreases extracellular norepinephrine and serotonin in addition to itseffects on dopamine. Recently work indicates that acute methylphenidateadministration increases extracellular dopamine and norepinephrine,consistent with its presumed mechanism of action as a uptake blocker ofthe nerve terminal transporters.

[0052] Peak blood levels following the administration of methylphenidatehave been noted at 1 to 3 hours (Faraj et al., 1974; Milberg et al.,1975). The half-life of the drug ranges from 2 to 4 hours (Faraj et al.,1974; Hungund et al., 1979; Soldin et al., 1979) in adults and children.Hungund et al. (1979) reported on the pharmacokinetics ofmethylphenidate in four hyperkinetic children. The mean half-life was2.5 hours. Although there was little variability in this parameter, bodyclearance varied by a factor of three. This suggested that plasmamethylphenidate levels are subject to a considerable degree ofinter-patient variability.

[0053] The primary route of metabolism for methylphenidate isde-esterification to ritalinic acid, which accounts for 75% to 91% oftotal urinary methylphenidate. Other metabolic products arise fromp-hydroxylation or oxidation to the lactam.

[0054] The methylphenidate formulations of the present invention may beadministered to children 6 years and over, and preferably have aduration of action from about 8 to about 12 hours, preferably from about8 to about 10 hours. The inventive methylphenidate formulation should betaken at breakfast time and is designed to replace two separate doses ofmethylphenidate immediate release given at breakfast and lunch time.Patients who require more frequent administration of immediate releasemethylphenidate than twice daily may be given an additional dose ofimmediate release methylphenidate at suppertime, when receiving theinventive methylphenidate formulation. The contents of theMethylphenidate MLR capsules may be sprinkled on soft foods beforeadministration.

[0055] The controlled/modified release preparations of the presentinvention may be used in conjunction with any multiparticulate system,such as granules, spheroids, beads, pellets, ion-exchange resin beads,and other multiparticulate systems in order to obtain a desiredsustained-release of the therapeutically active agent. Beads, granules,spheroids, or pellets, etc., prepared in accordance with the presentinvention can be presented in a capsule or in any other suitable unitdosage form. An amount of the multiparticulates effective to provide thedesired dose of drug over time may be placed in a capsule, may becontained in a packet and sprinkled onto food, or may be incorporated inany other suitable oral solid form, such as a tablet. On the other hand,the present invention can be in the form of a matrix tablet. Withrespect to all such optional formulations, it is desired that theformulation be prepared such that an initial immediate release of drugprovides an early onset of effect, which onset is analogous to animmediate release formulation, and that the formulation further providea sustained release component which maintains therapeutically effectivelevels of the drug in the plasma for the desired amount of time,followed by a relatively rapid drop-off in blood plasma levels relativeto typical sustained release formulations. Viewed as an in vivotime/concentration plot, the plasma level of the drug from theformulations of the present invention have the appearance of a “squarewave”. The immediate release component preferably represents from about30% to about 40% of the total dose and the controlled release componentpreferably represents from about 60% to about 70% of the total dose ofmethylphenidate contained in the formulations of the present invention.In certain preferred embodiments, including the MLR embodiments of theinvention, the immediate release component represents about 40% of thetotal dose and the controlled release component represents about 60% ofthe total dose of methylphenidate contained in the formulation.

[0056] In the case of methylphenidate, it is desired that the onset ofaction occurs from about 0.5 to about 4 hours, and preferably from about0.5 to about 2 hours after the oral dosage form is administered, and itis further desired that the dosage form no longer provides effectiveplasma levels of methylphenidate from about 8 to about 12, morepreferably from about 8 to about 10 hours, after oral administration ofthe dose. In this manner, the dose of methylphenidate can beadministered to a child in the morning before school begins, providesthe desired effect at the start of the school day, with thepharmacologic action of the drug not waning until after the school dayends, and preferably before dinner so that the drug does not have theside effect of acting as an appetite suppressant.

[0057] The formulations of the present invention are designed to producea rapid rise to therapeutic plasma levels after oral administration, dueto the rapid dissolution and absorption of the outer layer, followed bya period of reduced absorption and then controlled release of theimmediate release core, to maintain therapeutic plasma levels. Afterabsorption of the immediate release core, plasma levels would thenrapidly decrease according to the elimination kinetics ofmethylphenidate.

[0058] It is generally recognized that the mere presence of an activesubstance in the gastrointestinal fluids does not, by itself, insurebioavailability. Bioavailability, in a more meaningful sense, is thedegree, or amount, to which a drug substance is absorbed into thesystemic circulation in order to be available to a target tissue site.To be absorbed, an active drug substance must be in a solution. The timerequired for a given proportion of an active drug substance contained ina dosage unit to enter into solution in appropriate physiological fluidsis known as the dissolution time. The dissolution time for an activesubstance from a dosage unit is determined as the proportion of theamount of active drug substance released from the dosage unit over aspecified time by a test method conducted under standardized conditions.The physiological fluids of the gastrointestinal tract are the media fordetermining dissolution time. The present state of the art dissolutiontime for pharmaceutical compositions, and these test procedures aredescribed in official compendia world wide.

[0059] Although there are many diverse factors which influence thedissolution of a drug substance from its carrier, the dissolution timedetermined for a pharmacologically active substance from a specificcomposition is relatively constant and reproducible. Among the differentfactors affecting the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified inthis steady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologicalconditions, the saturation level of the dissolved materials isreplenished from the dosage form reserve to maintain a relativelyuniform and constant dissolution concentration in the solvent medium,providing for a steady state absorption.

[0060] The transport across a tissue absorption site in thegastrointestinal tract is influenced by the Donnan osmotic equilibriumforces on both sides of the membrane, since the direction of the drivingforce is the difference between the concentrations of active substanceon either side of the membrane, i.e. the amount dissolved in thegastrointestinal fluids and the amount present in the blood. Since theblood levels are constantly being modified by dilution, circulatorychanges, tissue storage, metabolic conversion and systemic excretion,the flow of active materials is directed from the gastrointestinal tractinto the blood stream.

[0061] Notwithstanding the diverse factors influencing both dissolutionand absorption of a drug substance, in many cases an importantcorrelation can be established between the in vitro dissolution timedetermined for a dosage form and the in vivo bioavailability. Thiscorrelation is so firmly established in the art that dissolution timehas become generally descriptive of bioavailability potential for manyclasses of active components contained in a particular dosage form. Inview of this relationship, the dissolution time determined for acomposition is one of the important fundamental characteristics forconsideration when evaluating whether a controlled release formationshould be tested in vivo.,

[0062] With the above in mind, the in-vitro dissolution of the drug atvarious time points for formulations in accordance with the presentinvention is provided below: Time (hours) % Methylphenidate HCldissolved 0.25  0-45% 1  5-50% 4 40-90% 8 NLT 60% 12 NLT 80%

[0063] In certain preferred embodiments of the present invention, thein-vitro dissolution of the drug at various time points for formulationsin accordance with the present invention is provided below: Time (hours)% Methylphenidate HCl dissolved 0.25  0-45% 1 10-50% 4 30-80% 8 NLT 65%12 NLT 80%

Sustained Release Coatings

[0064] In certain preferred embodiments, the drug is incorporated intoor onto a substrate and a sustained release coating is applied thereto.For example, the drug may be contained within or on a substrate asfollows: (i) incorporated-into matrix spheroids (e.g., together with apharmaceutically acceptable spheronizing agent such as microcrystallinecellulose), (ii) coated onto inert pharmaceutically acceptable-beads(e.g., nonpareil beads); (iii) incorporated into a normal release tabletcore; or (iv) incorporated into a tablet core which comprises a matrixincluding a sustained release carrier material. Thereafter, a sustainedrelease coating is applied onto substrates such as those mentioned in(i)-(iv) above. The dosage forms of the present invention may optionallycoated with one or more materials suitable for the regulation of releaseor for the protection of the formulation. In one embodiment, coatingsare provided to permit either pH-dependent or pH-independent release,e.g., when exposed to gastrointestinal fluid. A pH-dependent coatingserves to release the drug in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseregardless of pH-changes in the environmental fluid, e.g., the GI tract.It is also possible to formulate compositions which release a portion ofthe dose in one desired area of the GI tract, e.g., the stomach, andrelease the remainder of the dose in another area of the GI tract, e.g.,the small intestine.

[0065] Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

[0066] In certain preferred embodiments, the substrate (e.g., tabletcore bead, matrix particle) comprising the drug, is coated with ahydrophobic material selected from (i) an alkylcellulose; (ii) anacrylic polymer; or (iii) mixtures thereof. The coating may be appliedin the form of an organic or aqueous solution or dispersion. The coatingmay be applied to obtain a weight gain from about 2 to about 25% of thesubstrate in order to obtain a desired sustained release profile. Suchformulations are described, e.g., in detail in U.S. Pat. Nos. 5,273,760and 5,286,493, assigned to the Assignee of the present invention andhereby incorporated by reference. The particles are preferably filmcoated with a material that permits release of the drug so as toachieve, in combination with the other stated properties, a desiredin-vitro release rate and in-vivo plasma levels. The sustained releasecoating formulations of the present invention should be capable ofproducing a strong, continuous film that is smooth and elegant, capableof supporting pigments and other coating additives, non-toxic, inert,and tack-free.

[0067] Other examples of sustained release formulations and coatingswhich may be used in accordance with the present invention includeAssignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, herebyincorporated by reference in their entirety.

Alkylcellulose Polymers

[0068] Cellulosic materials and polymers, including alkylcelluloses,provide hydrophobic materials well suited for coating the beadsaccording to the invention. Simply by way of example, one preferredalkylcellulosic polymer is ethylcellulose, although the artisan willappreciate that other cellulose and/or alkylcellulose polymers may bereadily employed, singly or in any combination, as all or part of ahydrophobic coating according to the invention.

[0069] One commercially available aqueous dispersion of ethylcelluloseis Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® isprepared by dissolving the ethylcellulose in a water-immiscible organicsolvent and then emulsifying the same in water in the presence of asurfactant and a stabilizer. After homogenization to generate submicrondroplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatexduring the manufacturing phase. Thus, prior to using the same as acoating, it is necessary to intimately mix the Aquacoat® with a suitableplasticizer prior to use.

[0070] Another aqueous dispersion of ethylcellulose is commerciallyavailable as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). Thisproduct is prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(dibutyl sebacate), and stabilizer (oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly ontosubstrates.

Acrylic Polymers

[0071] The hydrophobic material comprising the controlled releasecoating may comprise a pharmaceutically acceptable acrylic polymer,including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer; poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

[0072] In certain preferred embodiments, the acrylic polymer iscomprised of one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers are well known in the art, and are described inNF XVII as fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups.

[0073] In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth)acrylic esters.

[0074] Certain methacrylic acid ester-type polymers are useful forpreparing pH-dependent coatings which maybe used in accordance with thepresent invention. For example, there are a family of copolymerssynthesized from diethylaminoethyl methacrylate and other neutralmethacrylic esters, also known as methacrylic acid copolymer orpolymeric methacrylates, commercially available as Eudragit® from RohmTech, Inc. There are several different types of Eudragit®. For example,Eudragit® E is an example of a methacrylic acid copolymer which swellsand dissolves in acidic media. Eudragit® L is a methacrylic acidcopolymer which does not swell at about pH<5.7 and is soluble at aboutpH>6. Eudragit® S does not swell at about pH<6.5 and is soluble at aboutpH>7. Eudragit® RL and Eudragit® RS are water swellable, and the amountof water absorbed by these polymers is pH-dependent, however, dosageforms coated with Eudragit® RL and RS are pH-independent.

[0075] In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

[0076] The Eudragit® RL/RS dispersions of the present invention may bemixed together in any desired ratio in order to ultimately obtain asustained release formulation having a desirable dissolution profile.Desirable sustained release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL: 90% Eudragit® RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

Plasticizers

[0077] In embodiments of the present invention where the coatingcomprises an aqueous dispersion of a hydrophobic material such as analkylcellulose or an acrylic polymer, the inclusion of an effectiveamount of a plasticizer in the aqueous dispersion of hydrophobicmaterial will further improve the physical properties of the sustainedrelease coating. For example, because ethylcellulose has a relativelyhigh glass transition temperature and does not form flexible films undernormal coating conditions, it is preferable to incorporate a plasticizerinto an ethylcellulose coating containing sustained release coatingbefore using the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentration of the plasticizer, however,can only be properly determined after careful experimentation with theparticular coating solution and method of application.

[0078] Examples of suitable plasticizers for ethylcellulose includewater insoluble plasticizers such as dibutyl sebacate, diethylphthalate, triethyl citrate, tributyl citrate, and triacetin, althoughit is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may beused. Triethyl citrate is an especially preferred plasticizer for theaqueous dispersions of ethyl cellulose of the present invention.

[0079] Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

[0080] It has further been found that the addition of a small amount oftalc reduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

[0081] When the aqueous dispersion of hydrophobic material is used tocoat a substrate including the drug, for example, inert pharmaceuticalbeads such as nu pariel {fraction (18/20)} beads, a plurality of theresultant stabilized solid controlled release beads may thereafter beplaced in a gelatin capsule in an amount sufficient to provide aneffective controlled release dose when ingested and contacted by anenvironmental fluid, e.g., gastric fluid or dissolution media.Alternatively, the substrate may be a tablet core coated with thesustained release coating, and optionally a further film-forming agentor colorant, such as Opadry®.

[0082] In formulations where an aqueous dispersion of an hydrophobicpolymer such as and alkylcellulose is applied to the substrate, it ispreferred that the coated substrate is cured at a temperature above theglass transition temperature of the plasticized polymer and at arelative humidity above ambient conditions, until an endpoint is reachedat which the coated formulation attains a dissolution profile which issubstantially unaffected by exposure to storage conditions, e.g., ofelevated temperature and/or humidity. Generally, in such formulationsthe curing time is about 24 hours or more, and the curing conditions maybe, for example, about 60° C. and 85% relative humidity. Detailedinformation concerning the stabilization of such formulations is setforth in U.S. Pat. Nos. 5,273,760; 5,681,585; and 5,472,712; all ofwhich are hereby incorporated by reference in their entireties.

[0083] In formulations where an aqueous dispersion of an acrylic polymeris applied to the substrate, it is preferred that the coated substrateis cured at a temperature above the glass transition temperature of theplasticized polymer until an endpoint is reached at which the coatedformulation attains a dissolution profile which is substantiallyunaffected by exposure to storage conditions, e.g., of elevatedtemperature and/or humidity. Generally, the curing time is about 24hours or more, and the curing temperature may be, for example, about 45°C. Detailed information concerning the stabilization of suchformulations is set forth in U.S. Pat. Nos. 5,286,493; 5,580,578; and5,639,476; all of which are hereby incorporated by reference in theirentireties.

[0084] The sustained release profile of the coated formulations of theinvention-can be altered, for example, by varying the amount ofovercoating with the aqueous dispersion of hydrophobic material,altering the manner in which the plasticizer is added to the aqueousdispersion of hydrophobic material, by varying the amount of plasticizerrelative to hydrophobic material, by the inclusion of additionalingredients or excipients, by altering the method of manufacture, etc.The dissolution profile of the ultimate product may also be modified,for example, by increasing or decreasing the thickness of the retardantcoating.

[0085] Spheroids or beads coated with a therapeutically active agent areprepared, e.g., by dissolving the therapeutically active agent in waterand then spraying the solution onto a substrate, for example, nu pariel{fraction (18/20)} beads, using a Wuster insert. Optionally, additionalingredients are also added prior to coating the beads in order to assistthe binding of the drug to the beads, and/or to color the solution, etc.For example, a product which includes hydroxypropylmethylcellulose, etc.with or without colorant (e.g., Opadry®, commercially available fromColorcon, Inc.) may be added to the solution and the solution mixed(e.g., for about 1 hour) prior to application of the same onto thebeads. The resultant coated substrate, in this example beads, may thenbe optionally overcoated with a barrier agent, to separate thetherapeutically active agent from the hydrophobic controlled releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

[0086] The beads may then be overcoated with an aqueous dispersion ofthe hydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethyl-cellulose,such as Aquacoat® or Surelease®, may be used. If Surelease is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragitcan be used.

[0087] The coating solutions of the present invention preferablycontain, in addition to the film-former, plasticizer, and solvent system(i.e., water), a colorant to provide elegance and product distinction.Color may be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color be added to Aquacoat via the use of alcoholor propylene glycol based color dispersions, milled aluminum lakes andopacifiers such as titanium dioxide by adding color with shear to watersoluble polymer solution and then using low shear to the plasticizedAquacoat. Alternatively, any suitable method of providing color to theformulations of the present invention may be used. Suitable ingredientsfor providing color to the formulation when an aqueous dispersion of anacrylic polymer is used include titanium dioxide and color pigments,such as iron oxide pigments. The incorporation of pigments, may,however, increase the retard effect of the coating.

[0088] The plasticized aqueous dispersion of hydrophobic material may beapplied onto the substrate comprising the therapeutically active agentby spraying using any suitable spray equipment known in the art. In apreferred method, a Wurster fluidized-bed system is used in which an airjet, injected from underneath, fluidizes the core material and effectsdrying while the acrylic polymer coating is sprayed on. A sufficientamount of the aqueous dispersion of hydrophobic material to obtain apredetermined sustained release of the therapeutically active agent(i.e., drug) when the coated substrate is exposed to aqueous solutions,e.g. gastric fluid, is preferably applied, taking into account thephysical characteristics of the therapeutically active agent, the mannerof incorporation of the plasticizer, etc. After coating with thehydrophobic material, a further overcoat of a film-former, such asOpadry, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

[0089] The release of the drug from the sustained release formulation ofthe present invention can be further influenced, i.e., adjusted to adesired rate, by the addition of one or more release-modifying agents,or by providing one or more passageways through the coating. The ratioof hydrophobic material to water soluble material is determined by,among other factors, the release rate required and the solubilitycharacteristics of the materials selected.

[0090] The release-modifying agents which function as pore-formers maybe organic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

[0091] The sustained release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

[0092] The sustained release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

[0093] The release-modifying agent may also comprise a semi-permeablepolymer.

[0094] In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

[0095] The sustained release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864 (all of which are hereby incorporated by reference). Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

[0096] The substrate of the present invention may be prepared by aspheronizing agent together with the active agent ingredient that can bespheronized to form spheroids. Microcrystalline cellulose is preferred.A suitable microcrystalline cellulose is, for example, the material soldas Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments, inaddition to the active ingredients and spheronizing agent, the spheroidsmay also contain a binder. Suitable binders, such as low viscosity,water soluble polymers, will be well known to those skilled in thepharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxypropylcellulose, are preferred. Additionally(or alternatively) the spheroids may contain a water insoluble polymer,especially an acrylic polymer, an acrylic copolymer, such as amethacrylic acid-ethyl acrylate copolymer or ethyl cellulose. In suchembodiments, the sustained-release coating will generally include awater insoluble material such as (a) a wax, either alone or in admixturewith a fatty alcohol; or (b) shellac or zein.

[0097] In a particular preferred embodiment of the invention, thecontrolled/modified release methylphenidate formulation is prepared as amultilayered release (MLR) formulation comprising coated inert beads. Asummary of one method of manufacturing such a formulation is outlined asfollows. First, immediate release (IR) methylphenidate beads areprepared by spraying a solution of methylphenidate in water over sugarbeads in a fluid bed dryer with a drug load of about 8%. The sprayprocess is carried out in a fluid bed dryer, equipped with a Wurstercolumn. A clear overcoat of HPMC is applied using an Qpadry® material(e.g., Opadry® Clear (Formula No: YS-1-7006)), to a weight gain of about1%. Next, a controlled release coating is applied to the IR beads, whichconverts the same into controlled release (CR) beads. This isaccomplished by spraying a solution of Eudragit® RS 30 D, triethylcitrate (plasticizer) and talc (glidant), onto the IR beads. Next, thecoated beads are cured in order to obtain a stabilized release rate ofthe therapeutically active agent. In preferred embodiments of thepresent invention where the CR coating utilizes an acrylic resin tocontrol the release of the drug, the CR beads at this stage aresubjected to oven curing at a temperature above the Tg of theplasticized acrylic polymer of the required time period, the optimumvalues of the temperature and time for the particular formulation beingdetermined experimentally. In certain embodiments of the presentinvention, the stabilized products is obtained via oven curing conductedat a temperature of about 40-50° C. for a time period of about 12 toabout 24 hours or longer. An enteric coating is then applied onto the CRbeads to convert the same into enteric coated CR (ECCR) beads. This isaccomplished by spraying a solution of Eudragit® L 30 D-55 dispersion,triethyl citrate (plasticizer) and talc (glidant) onto the CR beads.Finally, an immediate release coating is applied onto the ECCR beads(referred to as, e.g., an IR Topcoat). This is accomplished by sprayinga solution of methylphenidate in water over EC CR beads.

[0098] Results of initial studies show that this formulation is stableunder room temperature (25° C., 60% RH) and accelerated conditions (40°C., 75% RH).

Sustained Release Matrices

[0099] In certain preferred embodiments of the present invention, thesustained release formulation comprises a matrix including the drug anda sustained release carrier (which may comprise one or more hydrophobicmaterials, such as an alkylcellulose and/or an acrylic polymer aspreviously defined herein). The materials suitable for inclusion in asustained release matrix will depend on the method used to form thematrix.

[0100] Suitable materials for inclusion in the sustained releasematrices of the invention, in addition to the drug, include:

[0101] (A) hydrophilic and/or hydrophobic materials, such as gums;alkylcelluloses; cellulose ethers, including hydroxyalkylcelluloses andcarboxyalkylcelluloses; acrylic resins, including all of the acrylicpolymers and copolymers discussed above, and protein derived materials.This list is not meant to be exclusive, and any pharmaceuticallyacceptable hydrophobic material or hydrophilic material which is capableof imparting the desired sustained release profile of the drug is meantto be included herein. The dosage form may comprise, e.g., from about 1%to about 80% by weight of such material.

[0102] In certain preferred embodiments of the present invention, thehydrophobic material is a pharmaceutically acceptable acrylic polymer,including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate, methyl methacrylate copolymers,ethoxy-ethyl methacrylates, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.In other embodiments, the hydrophobic material is selected frommaterials such as hydroxyalkylcelluloses such ashydroxypropylmethylcellulose and mixtures of the foregoing. In yet otherembodiments, the hydrophobic material is an alkylcellulose.

[0103] (B) digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fattyalcohols, glyceryl esters of fatty acids, mineral and vegetable oils andnatural or synthetic waxes, polyhydric alcohols, including polyalkyleneglycols. The oral dosage form may contain up to 60% (by weight) of suchmaterial. In certain embodiments, a combination of two or morehydrocarbon materials are included in the matrix formulations. If anadditional hydrocarbon material is included, it is preferably selectedfrom natural and synthetic waxes, fatty acids, fatty alcohols, andmixtures of the same.

[0104] Preferred hydrocarbons are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends, and have a meltingpoint from about 30° C. to about 200° C., preferably from about 45° C.to about 90° C.

[0105] For purposes of the present invention, a wax-like substance isdefined as any material which is normally solid at room temperature andhas a melting point of from about 30° C. to about 100° C. Suitable waxesinclude, for example, beeswax, glycowax, castor wax and carnauba wax.

[0106] The aliphatic alcohol may be, for example, lauryl alcohol,myristyl alcohol or stearyl, cetyl and/or cetostearyl alcohol. Theamount of aliphatic alcohol, if included in the present oral dosageform, will be determined, as above, by the precise rate of drug releaserequired. In certain embodiments, the oral dosage form contains between20% and 50% (by wt) aliphatic alcohol. When at least one polyalkyleneglycol is present in the oral dosage form, then the combined weight ofthe at least one aliphatic alcohol and the at least one polyalkyleneglycol preferably constitutes between 20% and 50% (by wt) of the totaldosage.

[0107] In one embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the drug from the formulation.

[0108] Suitable polyalkylene glycols include, for example, polypropyleneglycol or polyethylene glycol. The number average molecular weight ofthe at least one polyalkylene glycol is preferred between 1,000 and15,000 especially between 1,500 and 12,000.

[0109] In addition to the above ingredients, a controlled release matrixmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

[0110] In order to facilitate the preparation of a solid, sustainedrelease, oral dosage form according to this invention, any method ofpreparing a matrix formulation known to those skilled in the art may beused. For example incorporation in the matrix may be effected, forexample, by (a) forming granules comprising at least one water solublehydroxyalkyl cellulose and drug or an drug salt; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂-C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose/drug with water. In a particularly preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the drug.

[0111] In yet other alternative embodiments, a spheronizing agent,together with the active ingredient can be spheronized to formspheroids. Microcrystalline cellulose is preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (Trade Mark, FMC Corporation). In such embodiments, in additionto the active ingredient and spheronizing agent, the spheroids may alsocontain a binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will-generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrices

[0112] In certain preferred embodiments of the present invention, thesustained release matrices also be prepared via melt-granulation ormelt-extrusion techniques. Such formulations are described in U.S.patent application Ser. No. 08/334,209, filed Nov. 4, 1994 and U.S.patent application Ser. No. 08/833,948, filed Apr. 10, 1997, both ofwhich are hereby incorporated by reference in their entireties.Generally, melt-granulation techniques involve melting a normally solidhydrophobic material, e.g. a wax, and incorporating a powdered drugtherein. To obtain a sustained release dosage form, it may be necessaryto incorporate an additional hydrophobic substance, e.g. ethylcelluloseor a water-insoluble acrylic polymer, into the molten wax hydrophobicmaterial. Examples of sustained release formulations prepared viamelt-granulation techniques are found in U.S. Pat. No. 4,861,598,assigned to the Assignee of the present invention and herebyincorporated by reference in its entirety.

[0113] The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

[0114] In addition to the above ingredients, a sustained release matrixmay also contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation. In addition to the above ingredients,a sustained release matrix incorporating melt-extruded multiparticulatesmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired.

[0115] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms are describedin the Handbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

[0116] The preparation of a suitable melt-extruded matrix according tothe present invention may, for example, include the steps of blendingthe drug analgesic (i.e., drug) together with at least one hydrophobicmaterial and preferably the additional hydrophobic material to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded toform strands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides sustained release of the therapeuticallyactive agent for a time period of from about 8 to about 24 hours. Themultiparticulates may be divided into unit doses via placement into agelatin capsule, or may be compressed into a suitable tablet form.

[0117] An optional process for preparing the melt extrusions of thepresent invention includes directly metering into an extruder ahydrophobic material, a therapeutically active agent, and an optionalbinder; heating the homogenous mixture; extruding the homogenous mixtureto thereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and dividing said particles into unit doses. In thisaspect of the invention, a relatively continuous manufacturing procedureis realized.

[0118] The diameter of the extruder aperture or exit port can also beadjusted to vary the thickness of the extruded strands. Furthermore, theexit part of the extruder need not be round; it can be oblong,rectangular, etc. The exiting strands can be reduced to particles usinga hot wire cutter, guillotine, etc.

[0119] The melt extruded multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded multiparticulate(s)” and “melt-extruded multiparticulatesystem(s)” and “melt-extruded particles” shall refer to a plurality ofunits, preferably within a range of similar size and/or shape andcontaining one or more active agents and one or more excipients,preferably including a hydrophobic material as described herein. In thisregard, the melt-extruded multiparticulates will be of a range of fromabout 0.1 to about 12 mm in length and have a diameter of from about 0.1to about 5 mm In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

[0120] In one preferred embodiment, oral dosage forms are prepared toinclude an effective amount of melt-extruded multiparticulates within acapsule. For example, a plurality of the melt-extruded multiparticulatesmay be placed in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

[0121] In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

[0122] In yet another preferred embodiment, the extrudate can be shapedinto tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et.al.), described in additional detail above and hereby incorporated byreference.

[0123] Optionally, the sustained release melt-extruded multiparticulatesystems or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained release coating such as the sustained releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic material to obtain a weight gain level from about2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular drug analgesic compoundutilized and the desired release rate, among other things.

[0124] The melt-extruded unit dosage forms of the present invention mayfurther include combinations of melt-extruded multiparticulatescontaining one or more of the therapeutically active agents disclosedabove before being encapsulated. Furthermore, the unit dosage forms canalso include an amount of an immediate release therapeutically activeagent for prompt therapeutic effect. The immediate releasetherapeutically active agent may be incorporated, e.g., as separatepellets within a gelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g.,controlled release coating or matrix-based). The unit dosage forms ofthe present invention may also contain a combination of controlledrelease beads and matrix multiparticulates to achieve a desired effect.

[0125] The sustained release formulations of the present inventionpreferably slowly release the therapeutically active agent, e.g., wheningested and exposed to gastric fluids, and then to intestinal fluids.The sustained release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic material, by varying the amount ofplasticizer relative to hydrophobic material, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc.

[0126] In other embodiments of the invention, the melt extruded materialis prepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

[0127] The substrates of the present invention may be also be preparedvia a melt pelletization technique. In such circumstances, the activedrug in finely divided form is combined with a binder (also inparticular form and other optional inert ingredients, and thereafter themixture is pelletized, e.g. by mechanically working the mixture in ahigh shear mixer to form the pellets (granules, spheres). Thereafter,the pellets (granules, spheres) may be sieved in order to obtain pelletsof the requisite size. The binder material is preferably in particulateform and has a melting point above about 40° C. Suitable bindersubstances include, for example, hydrogenated castor oil, hydrogenatedvegetable oil, other hydrogenated fats, fatty-acid esters, fatty acidglycerides, and the like.

[0128] Proposed strengths of the methylphenidate formulations of theinvention may be, e.g., 10, 15, 20 and 30 mg. In MLR methylphenidatemultiparticulate formulations of the invention, proposed capsule sizesand fill weights for such dosage strengths are as follows: Strength FillWeight Capsule Size 10 mg 100 mg 4 15 mg 150 mg 3 20 mg 200 mg 2 30 mg300 mg 1

[0129] In certain preferred embodiments of the present invention, aneffective amount of the drug in immediate release form is included inthe drug formulation. The immediate release form of the drug is includedin an amount which is effective to shorten the time to maximumconcentration of the drug in the blood (e.g., plasma), such that time toT_(max) is shortened to a time of, e.g., from about 0.5 to about 2hours. By including an amount of immediate release drug in theformulation, the time to onset of action is significantly reduced, andis the same or earlier than that of the reference standard IR treatment(Ritalin IR).

[0130] In such embodiments, an effective amount of the drug in immediaterelease form may be coated onto the substrates (e.g., multiparticulatesor tablets) of the present invention. For example, where the extendedrelease of the drug from the formulation is due to a controlled releasecoating, the immediate release layer can be overcoated on top of thecontrolled release coating. On the other hand, the immediate releaselayer may be coated onto the surface of substrates wherein the drug isincorporated in a controlled release matrix. Where a plurality of thesustained release substrates comprising an effective unit dose of thedrug (e.g., multiparticulate systems including pellets, spheres, beadsand the like) are incorporated into a hard gelatin capsule, theimmediate release portion of the drug dose may be incorporated into thegelatin capsule via inclusion of the sufficient amount of immediaterelease drug as a powder or granulate within the capsule. Alternatively,the gelatin capsule itself may be coated with an immediate release layerof the drug. One skilled in the art would recognize still otheralternative manners of incorporating the immediate release drug portioninto the unit dose. Such alternatives are deemed to be encompassed bythe appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0131] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 Methylphenidate HCl Immediate Release Beads

[0132] TABLE 1 Ingredients % Methylphenidate hydrochloride 15.0 Sugarbead 14/18 80.0 Opadry ® clear YS-1-7006 5.0 Water q.s. Total 100.0

[0133] 1. Charge Niro-Aeromatic Strea 1 Fluid Bed Wurster Coater with{fraction (14/18)} mesh Nupareil® PG (sugar spheres NF).

[0134] 2. Coat the beads at 60° C. by spraying a solution ofmethylphenidate hydrochloride (12% w/w) and Opadry clear (4% w/w) inwater.

[0135] 3. Once the coating is completed, allow the beads to dry at 60°C. for 2 or 3 minutes.

[0136] 4. Cool the beads in a shallow pan at room temperature.

[0137] 5. Break agglomerates, if any.

[0138] 6. Sift the beads through Tyler 10 mesh sieve (1.77 mm opening)and then through-Tyler 20 mesh sieve (850 micrometer opening) to removefines.

[0139] 7. Apply top coat to beads by spraying a solution of colouredOpadry clear solution (4% w/w) to a theoretical weight gain of 1% w/w.

[0140] After the completion of the overcoat, the beads are then filledinto hard gelatin capsules at a strength of 20 mg.

[0141] Dissolution testing was conducted on the bead filled IR capsulesusing USP Apparatus 1 (basket method) in 500 mL of simulated gastricjuice without enzyme, 100 rpm at 37° C. The results are as follows:TABLE 2 Time (minutes) % Methylphenidate HCl dissolved 10 92.7 20 95.730 97.7 45 98.5

[0142] The dissolution results as set forth in the above table indicatethat 98.5% of the methylphenidate hydrochloride was dissolved in 45minutes.

EXAMPLE 2 Methylphenidate HCl-Controlled-Release (CR) Beads with AcrylicPolymer Coating

[0143] TABLE 3 Ingredients % Methylphenidate IR beads 86.20 Eudragit ®RS 30 D 8.63 Triethyl citrate 1.72 Talc 3.45 Water q.s. Total 100.0

[0144] The controlled-release coating is manufactured as follows:

[0145] 1. The Eudragit® RS 30 D is plasticized with triethyl citrate andtalc approximately 30 minutes.

[0146] 2. A load of the IR beads is charged into a Wurster insert of anAeromatic Fluid Bed Dryer with 1 mm spray nozzle and the beads arecoated to a weight gain of −8%.

[0147] 3. Upon completion of the coating, the beads are cured for 24hours at 40-45° C.

[0148] The beads were then filled into hard gelatin capsules at a 20 mgstrength.

[0149] Dissolution testing was conducted on the bead filled CR capsulesusing the following USP Apparatus (basket method). The capsules wereplaced into 500 mL of simulated gastric juice without enzyme, for first2 hours at 100 rpm and 37° C. and then placed into 500 mL simulatedintestinal fluid without enzyme for the remainder of the testing period.The results are as follows: TABLE 4 Time (hours) Methylphenidate HCldissolved 1 6.9 2 16.2 3 26.1 4 35.7 6 59.8 8 74.7 12 75.4 18 82.5 2492.8

[0150] The dissolution results as set forth in the above table indicatethat 92.8% of methylphenidate hydrochloride dissolved in 24 hours.

EXAMPLES 3& 4 Dependence of Release Rate of Methylphenidate HCl fromControlled-Release (CR) Beads on Amount of Acrylic Polymer Coating

[0151] By adjusting the amount of Eudragit® RS 30 D applied, the releaserate can be adjusted. This effect is illustrated in Examples 3 and 4below: TABLE 5 % Ingredients Example 3 Example 4 Methylphenidate HCl IR91.2 94.0 Bead Eudragit ® RS 30 D 5.8 3.9 Triethyl citrate 1.0 0.7 Talc2.0 1.4 Water — — Total 100.0 100.0

[0152] The method of manufacturing the controlled-release beads inExamples 3 and 4 is similar to the method described under Example 2, byvarying the proportion of beads and Eudragit® RS 30D.

[0153] The cured beads were filled into hard gelatin capsules at astrength of 20 mg. The dissolution results, conducted under conditionsidentical to those found under Example 2, are shown below: TABLE 6 %Methylphenidate HCl Time dissolved (hours) Example 3 Example 4 1 18.749.5 2 35.1 73.3 3 49.0 81.5 4 60.6 85.2 6 75.7 90.4 8 77.3 90.7 12 82.192.8

[0154] The dissolution results as set forth in the above table, indicatethat 82.1% and 92.8% respectively of methylphenidate hydrochloride isdissolved in 12 hours. However, the release of drug from Example 4 wassignificantly faster at time points 1, 2, 3, 4, 6 and 8 hours.

EXAMPLE 5 Enteric Coated (EC) Coated Release (CR) Beads—EC•CR Beads

[0155] TABLE 7 Ingredients % Methylphenidate CR beads 83.2 Eudragit ® L30 D55 9.9 Triethyl citrate 2.0 Talc 4.9 Water q.s. Total 100.0

[0156] The enteric coating procedure is described below:

[0157] 1. The Eudragit® L 30 D 55 is plasticized with triethyl citrateand talc approximately 30 minutes.

[0158] 2. A load of the methylphenidate CR beads is charged into aWurster insert of an Aeromatic Fluid Bed Dryer with 1 nm spray nozzleand the beads are coated to a weight gain of ˜9%.

[0159] 3. Upon completion of the coating, the beads are cured for 18hours at 40° C.

[0160] 4. The cured beads are then sieved through Tyler 10 mesh (1.7 mmopening) and Tyler 20 mesh (850 micrometer opening) sieves to remove anyfines.

[0161] The beads were then filled onto hard gelatin capsules at a 20 mgstrength.

[0162] Dissolution testing was conducted on the bead filled CR filledcapsules using USP Apparatus 1 (basket method) 500 mL at 100 rpm and 37°C. using SGF without enzyme for the first 2 hours and SIF without enzymefor the rest of the testing period. Results are shown below: TABLE 8 %Methylphenidate Time HCl dissolved (hours) Lot 1 Lot 2 Lot 3 1 0.4 1.02.0 2 2.2 5.4 7.4 3 18.8 27.8 61.3 4 36.7 48.3 87.0 6 59.5 75.5 98.8 876.9 90.1 100.0 12 82.3 99.6 —

[0163] The dissolution results as set forth in the above table indicatethat very little drug is dissolved in gastric juice after entericcoating and that the dissolution profile of the CR beads has beenmodified.

EXAMPLE 6 Formulations for Clinical Trials

[0164] Examples 6A, 6B and 6C below set forth the formulations developedand tested in clinical studies.

Example 6A IR•EC•CR Beads Immediate Release (IR) Coating of EntericCoated Controlled-Release (EC•CR) Methylphenidate Beads

[0165] The (IR•EC•CR Beads) formulation, hereinafter referred to asFormulation 1, is a capsule containing multi-layer release beads whichhave both immediate release and controlled release components. It ismade up of a controlled release bead which is enteric coated to delaydissolution until after gastric emptying. The enteric coated controlledrelease bead has an immediate release topcoat to provide an initial rateof absorption equal to or greater than Ritalin® IR immediate releasetablets. The immediate release component represent 40% of the total doseper bead and the controlled release component represents 60%. TABLE 9Ingredients % Enteric coated Controlled Release 91.4 Methylphenidate HClbeads Methylphenidate hydrochloride USP 6.5 Opadry ® clear YS-1-7006 2.1Water q.s. Total 100.0

[0166] The application of an immediate release coat on the top ofEnteric Coated CR beads is described below:

[0167] 1. Dissolve methylphenidate HCl USP and Opadry in water withstirring.

[0168] 2. Load EC-CR beads into a Wurster insert of an Aeromatic FluidBed Dryer.

[0169] 3. Spray the beads with the coating solution using a 1 mm spraynozzle at a temperature of not more than 50° C.

[0170] 4. Once the coating is completed, cool the beads at roomtemperature and pass through Tyler sieves 10 and 20 mesh to removefines.

[0171] The beads were then filled into a hard gelatin capsule to a 20 mgstrength.

[0172] Dissolution testing was conducted on the bead filled capsules ofFormulation 1 using USP Apparatus 1 (basket method) 100 rpm, 500 mL at37° C.—simulated gastric juice without enzyme 1st and 2nd hours; 3rdhour onwards simulated intestinal fluid without enzyme.

[0173] The results are as follows: TABLE 10 Time (hours) %Methylphenidate HCl dissolved  5 minutes 37.0 10 minutes 38.0 15 minutes39.0 30 minutes 40.0 60 minutes 40.0 2 40.1 3 51.4 4 61.0 6 75.6 8 87.012  87.5

[0174] The dissolution results as set forth in the above table indicatea rapid onset on dissolution, followed by prolonged action.

Example 6B IR•EC•CR Blend Combination of Immediate ReleaseMethylphenidate Beads (IR) and Enteric Coated Controlled-Release (ECCR)Methylphenidate Beads

[0175] The enteric-coated controlled release beads (EC-CR) beadsdescribed in Example 5 may be mixed with the immediate release (IR)beads described in Example 1 in varying proportions and placed incapsules to obtain the final blended dosage form, (IR•EC•CR Blend),hereinafter referred to as Formulation 2. Formulation 2 was designed toprovide a faster rate of absorption of the controlled release portionthan Formulation 1. The immediate release component represents 35% ofthe total dose per capsule and the controlled release componentrepresents 65%.

[0176] Dissolution testing was performed and the comparative results areshown in Table 11 below.

Example 6C IR•CR Beads Immediate Release (IR) Coating ofControlled-Release (CR) Methylphenidate Beads

[0177] The IR•CR Beads formulation, hereinafter referred to asFormulation 3, is a capsule containing single beads made up of animmediate release topcoat and a controlled release core, and is designedto provide an intermediate rate of absorption of the controlled releaseportion between that of the controlled release formulations ofFormulations 1 and 2. The immediate release component represents 30% ofthe total dose per bead and the controlled release component represents70%.

[0178] The immediate release topcoat is applied to CR beads as describedin Example 6A for Formulation 1.

[0179] The dissolution profiles of Formulations 1-3 and Ritalin® SR,used as a comparator, are shown in Table 11 below. Hours 1 and 2 are in500 ml of simulated gastric fluid. Simulated intestinal fluid (500 ml)is used from the third hour onwards. The results of the dissolutiontesting confirmed the anticipated in vitro dissolution profile. TABLE 11Comparative Dissolution of Formulations Formulation Formulation Time(Hours) Ritalin SR Formulation 1 2 3 10 min 21.4 38.0 32.0 28.6 30 min31.4 40.0 36.7 34.0 1 45.7 40.0 38.2 40.5 2 62.3 40.1 40.4 57.6 3 75.851.4 68.1 70.6 4 79.5 61.0 86.4 79.5 6 88.0 75.6 95.4 89.6 8 90.7 87.096.2 92.7 12  91.3 87.5 97.0 93.1

EXAMPLE 7

[0180] Four Way Comparison of Single Dose Formulation 1 (Fed and Fasted)With Two Doses of Ritalin IR (Fed and Fasted)

[0181] The bioavailability of Methylphenidate MLR capsules wasinvestigated in a four-way blind study which compared the Formulation120 mg single dosage formulation under fed and fasted conditions withtwo doses (4 hours apart) of Ritalin® IR.

[0182] Healthy male volunteers were given a single dose of 20 mgFormulation 1 or two doses of immediate release methylphenidate 10 mgadministered four hours apart under both fed and fasting conditions(n=12). “Fed” conditions indicates the test formulation was given to thesubjects after they had eaten a high-fat breakfast. Following anovernight fast of at least 10.0 hours, each of the normal, healthy,non-smoking, male subjects were given the following treatment accordingto Williams design 4 treatment randomization scheme.

[0183] Treatment 1: Test Product: methylphenidate controlled-release,Formulation 1, 20 mg the morning under fasting conditions.

[0184] Treatment 2: Reference Product: methylphenidateimmediate-release, Ritalin® (Novartis), 10 mg tablet in the morning and4 hours later, under fasting conditions.

[0185] Treatment 3: Test Product: methylphenidate controlled-release,Formulation 1, 20 mg capsule, administered 5 minutes after a high fatbreakfast.

[0186] Treatment 4. Reference Product: methylphenidateimmediate-release, Ritalin® (Novartis), 10 mg tablet in the morning and4 hours later, administered 5 minutes after a high fat breakfast.

[0187] There was a seven day washout period between the study periods.During each study period, blood samples (1×5 mL each) were taken fromeach subject within one hour prior to dosing and at 0.250, 0.500, 0.750,1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00,10.0, 12.0, 16.0, 24.0 hours post-dose for the Formulation 1 and atpre-dose, 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00,4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 16.0, 24.0 hours post-dose forthe Ritalin® IR. Plasma was harvested from each blood sample and storedin a −20° C. freezer until assayed for plasma methylphenidateconcentration. Assay of plasma methylphenidate concentrations wasperformed using gas chromatography/mass spectrometry (GC/MS).

[0188] The mean plasma concentrations, standard deviations andcoefficients of variation are shown as a function of time in Tables 12and 13, for fasting and fed conditions, respectively.

[0189] This data is presented graphically in FIGS. 1-4. FIG. 1 presentsthe mean plasma concentration versus time for Formulation 1 and Ritalin®under fasting conditions. FIG. 2 presents the mean plasma concentrationversus time for Formulation 1 and Ritalin® under fed conditions. FIG. 3presents the mean plasma concentration versus time for Formulation 1under fed and fasting conditions. FIG. 4 presents the mean plasmaconcentration versus time for Ritalin® under fed and fasting conditions.TABLE 12 Mean Plasma Concentrations (pg/mL) of Methylphenidate:Formulation 1 and Ritalin ® IR (fasting) Formulation 1 Ritalin SampleTime Concen- Concen- (h) tration SD (±) CV (%) tration SD (±) CV (%)0.000 0.00 0.00 — 0.00 0.00 — 0.250 0.00 0.00 — 0.00 0.00 — 0.500 817.53801.84 98.08 883.96 686.65 77.68 0.750 2268.79 1128.12 49.72 2485.74828.38 33.33 1.00 3108.79 756.66 24.34 3468.74 1172.28 33.80 1.503597.88 740.36 20.58 4388.04 998.86 22.76 2.00 3675.60 1315.29 35.784289.39 1144.40 26.68 2.50 3469.81 882.62 25.44 4121.37 1014.57 24.523.00 3573.56 1031.61 28.87 3528.56 863.25 24.46 3.50 3637.01 1008.7327.74 3020.93 716.36 23.71 4.00 3604.03 1071.59 29.73 2747.91 698.9525.44 4.50 3494.44 1069.13 30.60 2958.49 799.89 27.04 5.00 3446.411069.50 31.03 4394.22 1603.40 36.49 5.50 — — — 5525.84 1766.58 31.976.00 3421.13 1166.25 34.09 5927.06 1955.99 33.00 6.50 — — — 5528.411758.49 31.81 7.00 3422.32 958.42 28.00 4860.45 1482.24 30.50 8.003338.59 724.49 21.70 3795.34 1500.79 39.54 10.0 2858.42 612.21 21.422223.48 926.11 41.65 12.0 2073.97 536.08 25.85 1334.71 523.37 39.21 16.01180.67 502.11 42.53 455.86 287.79 63.13 24.0 275.87 201.51 73.04 55.1099.99 181.46

[0190] TABLE 13 Mean Plasma Concentrations (pg/mL) of Methylphenidate:Formulation 1 and Ritalin ® IR (fed) Formulation 1 Ritalin Sample TimeConcen- Concen- (h) tration SD (±) CV (%) tration SD (±) CV (%) 0.0000.00 0.00 — 0.00 0.00 — 0.250 0.00 0.00 — 53.12 133.84 251.95 0.500291.66 271.58 93.11 1256.61 1602.66 127.54 0.750 910.22 653.80 71.832984.60 3406.53 114.14 1.00 1580.66 983.13 62.20 3400.39 2301.87 67.691.50 2760.68 797.24 28.88 5205.16 1882.17 36.16 2.00 3098.73 874.4928.22 5146.55 1617.43 31.43 2.50 3655.68 982.31 26.87 5157.11 1227.9923.81 3.00 3625.88 797.55 22.00 4546.61 932.94 20.52 3.50 3717.71 951.5825.60 4184.34 1080.71 25.83 4.00 3650.63 875.97 23.99 3652.57 1023.2228.01 4.50 3627.41 835.40 23.03 3811.27 1103.83 28.96 5.00 3430.14783.72 22.85 5158.45 1714.53 33.24 5.50 — — — 5982.98 1618.65 27.05 6.003418.03 937.07 27.42 6228.81 1591.64 25.55 6.50 — — — 6054.32 1919.9531.71 7.00 4218.94 775.86 18.39 5538.57 1741.02 31.43 8.00 4679.671126.52 24.07 4350.90 1611.95 37.05 10.0 3858.58 1045.56 27.10 2577.66896.59 34.78 12.0 2610.98 902.53 34.57 1521.52 611.54 40.19 16.0 1372.86737.71 53.74 577.90 334.26 57.84 24.0 334.79 306.63 91.59 94.23 144.99153.86

EXPERIMENTAL RESULTS

[0191] Pharmacokinetic parameters were calculated based on the data fromthe four-way study. AUC_(0-t) (pg·h/mL), AUC_(0-inf) (pg·h/mL),AUC_(t/inf) (%), C_(max) (pg/mL), T_(max) (hours), T_(1/2 el) (hours),K_(el) (hour⁻¹), TLIN (hours) and LQCT (hours) were calculated asdescribed below.

[0192] For purposes of the present invention, the following terms aremeant to have the following meanings:

[0193] Analysis of Pharmacokinetic Data and Statistical Analysis

[0194] AUC_(0-t) Area under the concentration-time curve from time zeroto the time of the last non-zero concentration (this corresponds to thearea under the concentration-time curve, over the dosing interval of thetest formulation for both controlled-release and immediate-releaseformulations)

[0195] AUC_(0-inf). Area under the concentration-time curve from timezero to infinity

[0196] C.I. Confidence interval

[0197] CV Coefficient of variation

[0198] C_(max) Maximum observed concentration

[0199] K_(el) Elimination rate constant

[0200] LQCT The last quantifiable concentration time

[0201] SD Standard deviation

[0202] TLIN The time point where log-linear elimination begins

[0203] T_(1/2 el) Time for observed C_(max)

[0204] Sampling Time Time post dose of plasma collection based onparameters to be studied

[0205] Scheduled Time The predetermined (clock) time at which thesamples are to be taken

[0206] Actual time The exact (clock) time at which the sample was taken

[0207] Time deviations during sampling for drugs with a T_(max)≦4 hourswere treated as follows: between 0 and 6 hours post dose, the samplingtime was used in the statistical analysis if the delay between theactual and scheduled time of blood collection was <10%. Above 6 hourspost dose, the sampling time was used in the statistical analysis if thedelay between the actual and scheduled time of plasma collection was<15%. When sampling times were used when previously described acceptancecriteria, the corrected sampling items were used when performingpharmacokinetic parameters calculations. Sampling times are present inconcentration tables and graphs of statistical report.

[0208] The mean, standard deviation (SD), and coefficient of variation(CV) were calculated for plasma concentrations of methylphenidate foreach sampling time and treatment. As well, the mean, SD, and CV werecalculated for the AUC_(0-t) (pg·h/mL), AUC_(0-inf) (pg·h/mL), C_(max)(pg/mL), T_(max) (hours), T_(1/2 el) (hours), K_(el) (hour⁻¹), TLIN(hours) and LQCT (hours). The calculation of these pharmacokineticparameters is explained below.

[0209] Areas Under the Concentration-Time Curves

[0210] AUC_(0-t) was calculated using the linear trapezoidal rule.

[0211] The AUC_(0-t) was derived where t is the time (t) of the lastmeasurable (non-zero) concentration (C_(t)) for each treatment.

[0212] The AUC_(0-inf) was calculated as:${AUC}_{0 - t} + \frac{C_{t}}{K_{el}}$

[0213] Where C_(t)=the last non-zero concentration for that treatment,AUC_(0-t)=the AUC from time zero to the time of the last non-zeroconcentration for that treatment and K_(el)=the elimination rateconstant.

[0214] Maximum Observed Concentration and Time of Observed PeakConcentration

[0215] The maximum observed concentration, C_(max), and the observedtime to reach peak concentration, T_(max), was determined for eachsubject and for each treatment.

[0216] Half-Life and Elimination Rate Constant

[0217] To calculate the elimination rate constant (K_(el)), linearregression analyses were performed on the natural log (Ln) of plasmaconcentration values (y) versus time (x). Calculations were made betweena time point where log-linear elimination phase begins (LQCT) occurred.The K was taken as the slope multiplied by (−1) and the apparenthalf-life (T_(1/2 el)) as 0.693/K_(el).

[0218] TLIN and LQCT

[0219] TLIN, the time point where log-linear elimination begins, andLQCT, the last quantifiable concentration time were determined for eachsubject and for each treatment.

[0220] Percent Drug Absorbed

[0221] Percent drug absorbed was calculated at each sampling time (t) byModified Wagner-Nelson's method, as' implemented in Kinetica software,version 2.0.1 according to the following formula:$\frac{C_{t} + \left( {K_{el} \times {AUC}_{0 - t}} \right)}{\left( {K_{el} \times {AUC}_{0 - \inf}} \right)} \times 100$

[0222] All ANOVAs were performed with the SAS General Linear ModelsProcedure (GLM). For all analyses, effects were considered statisticallysignificant if the probability associated with ‘F’ was less than 0.050.Based on the pairwise comparisons of the ln-transformed AUC_(0-t),AUC_(0-inf) and C_(max) data, the relative ratios of the geometricmeans, calculated according to the formulation “e^((X-Y))×100”, as wellas the 90% geometric confidence intervals were determined.

RESULTS

[0223] The plasma concentration of unchanged methylphenidate followingadministration of the controlled release formulation Formulation 1reached the maximum concentration (C_(max)) at a mean of 3:27 hoursunder fasting conditions and 7.29 hours under fed conditions reflectinga biphasic absorption profile. The plasma concentration of unchangedmethylphenidate following administration of two doses of the immediaterelease formulation (Ritalin® IR) reached the maximum concentration(C_(max)) at 5.96 hours under fasting conditions and 3.54 hours underfed conditions. When the determination of C_(max) was restricted to thefirst dose of immediate release methylphenidate, the T_(max) was 1.71hours under fasting conditions and 1.63 hours under fed conditions.

[0224] The complete pharmacokinetic parameters of controlled releasemethylphenidate 20 mg Formulation 1 and immediate releasemethylphenidate 10 mg (Ritalin® IR) under fed and fasted conditions aresummarized in Tables 14 and 15 below. TABLE 14 PharmacokineticParameters for Formulation 1 Formulation 1 (fasting) Formulation 1 (fed)Parameters Mean ± SD CV (%) Mean ± SD CV (%) AUC_(0-t) (pg · h/mL)48493.80 ± 13430.27 27.69 54686.38 ± 15118.66 27.65 AUC_(0-inf) (pg ·h/mL) 51213.86 ± 13260.14 26.59 57931.47 ± 16762.54 28.94 C_(max)(pg/mL) 4410.25 ± 1188.68 26.95 4879.37 ± 1027.85 21.07 T_(max) (h) 3.27± 2.54 77.64 7.29 ± 1.29 17.65 K_(el) (h⁻¹) 0.1672 ± 0.0339 20.25 0.1812± 0.0392 21.65 T_(1/2el)(h) 4.32 ± 0.96 22.18 4.06 ± 1.25 30.91

[0225] TABLE 15 Pharmacokinetic Parameters for Ritalin ® IR RITALIN ®(fasting) RITALIN ® (fed) Parameters Mean ± SD CV (%) Mean ± SD CV (%)AUC_(0-t) (pg · h/mL) 44644.22 ± 13806.82 30.93 52781.49 ± 15194.9428.79 AUC_(0-inf) (pg · h/mL) 46466.23 ± 14012.73 30.16 54783.17 ±15311.08 27.95 C_(max) (pg/mL) 6536.04 ± 1669.29 25.54 7571.74 ± 1534.5820.27 T_(max) (h) 5.96 ± 0.54 9.09 3.54 ± 2.42 68.43 K_(el) (h⁻¹) 0.2481± 0.0550 22.17 0.2449 ± 0.0719 29.37 T_(1/2el)(h) 2.93 ± 0.71 24.10 3.08± 0.96 31.26

[0226] The results of the ANOVA and Duncan's Multiple Range Testperformed on the ln-transformed AUC, data show a statisticallysignificant difference between treatments for this parameter. Accordingto Dunican's Multiple Range Test, the AUC_(0-t) of treatment 1 wassignificantly different from the AUC_(0-t) of treatments 2 and 3.However, Duncan's Multiple Range Test did not detect statisticallysignificant differences between treatments 3 and 4 for this parameter.The statistical analyses performed on the data are summarized in Table16 below: TABLE 16 AUC_(0-t) (pg · h/mL) TRT 1 vs. TRT 2 TRT 3 vs. TRT 4TRT 1 vs. TRT 3 Ratio 109.90% 104.08% 88.65% 90% 102.59% to  97.15% to82.75% to Geometric 117.74% 111.50% 94.97% C.I.

[0227] The results of the ANOVA and Duncan's Multiple Range Testperformed on the ln-transformed AUC_(0-inf) data show a statisticallysignificant difference between treatments for this parameter. Accordingto Duncan's Multiple Range Test, the AUC_(0-inf) of treatment 1 wassignificantly different from the AUC_(0-inf) of treatments 2 and 3.However, Duncan's Multiple Range Test did not detect statisticallysignificant differences between treatments 3 and 4 for this parameter.The statistical analyses performed on the data are summarized below inTable 17: TABLE 17 AUC_(0-inf) (pg · h/mL) TRT 1 vs. TRT 2 TRT 3 vs. TRT4 TRT 1 vs. TRT 3 Ratio 111.65% 105.86% 88.85% 90% 104.09% to  98.70% to82.84% to Geometric 119.95% 113.55% 95.30% C.I.

[0228] The results of the ANOVA and Duncan's Multiple Range Testperformed on the ln-transformed C_(max) data show a statisticallysignificant difference between treatments for this parameter. Accordingto Duncan's Multiple Range Test, the C_(max), of treatment 1 was notsignificantly different from the C_(max) of treatment 3. However,Duncan's Multiple Range Test detected statistically significantdifferences for C_(max) when comparing treatments 1 and 2 and treatments3 and 4. The statistical analyses performed on the data are summarizedbelow in Table 18: TABLE 18 C_(max) (pg/mL) TRT 1 vs. TRT 2 TRT 3 vs.TRT 4 TRT 1 vs. TRT 3 Ratio 67.48% 64.38%  89.37% 90% 60.28% to 57.51%to  79.83% to Geometric 75.54% 72.07% 100.04% C.I.

[0229] The ANOVA and Duncan's Multiple Range Test performed on theT_(max) data detected a statistically significant difference betweentreatments for this parameter. Duncan's Multiple Range Test detectedstatistically significant differences between treatments 1 and 2,treatments 3 and 4, and treatments 1 and 3 for this parameter.

[0230] The ANOVA and Duncan's Multiple Range Test performed on theT_(1/2 el) data detected a statistically significant difference betweentreatments for this parameter. Duncan's Multiple Range Test detected nostatistically significant differences between treatments 1 and 3 forT_(1/2 el) However, Duncan's Multiple Range Test detected statisticallysignificant differences between treatments 1 and 2 and treatments 3 and4 for this parameter.

[0231] The results of the ANOVA and Duncan's Multiple Range Testperformed on the K_(el) data show a statistically significant differencebetween treatments for this parameter. Statistically significantdifferences were detected by Duncan's Multiple Range Test betweentreatments 1 and 2 and treatments 3 and 4, but not for treatments 1 and0.3.

[0232] Summary and Analysis

[0233] The AUC and C_(max) ratios of controlled release methylphenidate20 mg Formulation 1 under fed and fasted conditions are summarized inTable 19 below. A comparison of the AUC and C_(max) ratios for immediaterelease methylphenidate 10 mg (Ritalin® IR) and Formulation 1 underfasting conditions are summarized in Table 20 below. Table 21 shows thecomparative ratios for immediate release methylphenidate 10 mg (Ritalin®IR) and Formulation 1 under fed conditions.

[0234] Treatment 1 (Formulation 1, Fasting) Versus Treatment 3(Formulation 1, Fed)

[0235] The ANOVAs detected statistically significant differences betweentreatments for ln-transformed AUC_(0-t), AUC_(0-inf) and C_(max), anduntransformed T_(max), K_(el), T_(1/2 el). Duncan's Multiple Range Testdetected statistically significant differences between treatments 1 and3 for ln-transformed AUC T and AUC_(0-inf) and untransformed T_(max).However, Duncan's Multiple Range Test detected no statisticallysignificant differences between treatments for ln-transformed C_(max)and untransformed K_(el) and T_(1/2 el). All formulation ratios, as wellas 90% geometric confidence intervals of the relative mean AUC_(0-t),AUC_(0-inf) and C_(max) of the test product (Formulation 1, fasting) toreference product (Formulation 1, fed) were found to be within 80 to125%. This is summarized in Table 19 below: TABLE 19 Formulation 1 (Fed)vs. Formulation 1 (Fast) AUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 112.80%112.54% 111.90% 90% 105.29%-120.84% 104.93%-120.71% 99.96%-125.27%Geometric C.I.²

[0236] Treatment 1 (Formulation 1, Fasting) Versus Treatment 2(Ritalin®, Fasting)

[0237] The ANOVAs detected statistically significant differences betweentreatments for ln-transformed AUC_(0-t), AUC_(0-inf) and C_(max) anduntransformed T_(max), K_(el), T_(1/2el). Duncan's Multiple Range Testdetected statistically significant differences between treatments 1 and2 for all parameters. With the exception of C_(max), all formulationratios as well as 90% geometric confidence intervals of the relativemean AUC_(0-t) and AUC_(0-inf) of the test product (Formulation 1) toreference product (Ritalin) were found to be within the 80 to 125%. Thisis summarized in Table 20 below: TABLE 20 Formulation 1 (Fast) vsRitalin ® (Fast) AUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 109.90% 111.65%67.48% 90% 102.59%- 104.09%- 60.28%- Geometric C.I.² 117.74% 119.75%75.54%

[0238] Treatment 3 (Formulation 1, Fed) Versus Treatment 4 (Ritalin®,Fed)

[0239] The ANOVAs detected statistically significant differences betweentreatments for ln-transformed AUC_(0-t), AUC_(0-inf) and C_(max), anduntransformed T_(max), K_(el), T_(1/2el). Duncan's Multiple Range Testdetected statistically significant differences between treatments 3 and4 for all parameters with the exception of ln-transformed AUC_(0-t) andAUC_(0-inf). With the exception of C_(max), all formulation ratios, aswell as 90% geometric confidence intervals of the relative meanAUC_(0-t) and AUC_(0-inf) of the test product (Formulation 1) toreference product (Ritalin) were found to be within the 80% to 125%.This is summarized in Table 21 below: TABLE 21 Formulation 1 (Fed) vs.Ritalin ® IR (Fed) AUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 104.08% 105.86%64.38% 90%  97.15%-  98.70%- 57.51%- Geometric C.I.² 111.50% 113.55%72.07%

CONCLUSIONS

[0240] Review of individual plasma MPH time curves indicates thefollowing:

[0241] Plasma MPH concentrations at 12 hours were higher on Formulation1 than on Ritalin IR in all subjects, under both fed and fastedconditions.

[0242] A biphasic profile was apparent under fasted conditions in7{fraction (10/12)} subjects and in 8{fraction (10/12)} under fedconditions. The mean curve showing a stable plateau under fastedconditions is therefore not fully representative of the individualprofiles. The enteric coat therefore gave rise to a biphasic profile insome subjects even under fasted conditions.

[0243] Under fasted conditions the apparent rate of rise of plasma MPHwas equivalent to, or faster than, that of Ritalin IR in {fraction(8/12)} subjects under fasted conditions and 4{fraction (5/12)} subjectsunder fed conditions. The mean curves which demonstrate an equivalentrate of rise under fasted conditions and a slower rise under fedconditions were therefore largely reflective of the individual profiles.

[0244] The bioavailability of Formulation 1 relative to Ritalin IR wasacceptable under both fed and fasted conditions (Relative AUC_(inf) 106%and 112%). There was an increase in AUC of both Formulation 1 andRitalin when given with food (13.1% and 17.9% respectively).

[0245] Formulation 1 had a more prolonged mean plasma MPH concentrationtime profile than two doses of Ritalin IR. An across study comparisonindicates that Formulation 1 also has a more prolonged profile thanRitalin SR.

[0246] Under fasted conditions Formulation 1 had a mean initial rate ofrise of plasma MPH that is similar to Ritalin IR and a relatively flatplateau until 8 hours post-dose.

[0247] Under fed conditions, the initial rise in plasma NTH fromFormulation 1 was slower than under fasted conditions and the plateaushowed a biphasic profile. This was consistent with predictions that theenteric coat would delay release of the controlled release component andthat this delay would be longer under fed conditions (allowing theinitial plasma concentration peak, due to the IR component, to fallprior to the start of release from the controlled release component).

[0248] Formulation 1 results in both a fast initial rate of rise ofplasma methylphenidate concentration, and a prolonged duration. Thetransformation from a prolonged plateau profile under fasted conditionsto a biphasic profile under fed conditions, is as predicted. Formulation1 therefore has the potential to meet the dual objectives of rapid onsetand prolonged duration that are considered desirable characteristics ofa controlled release methylphenidate formulation for the treatment ofADD/ADHD.

[0249] An initial pilot bioavailability study completed in adult healthyvolunteers has confirmed that a single 20 mg dose of this formulationhas an equivalent extent of absorption to two doses of immediate releasemethylphenidate (10 mg) given 4 hours apart. Maximal plasmaconcentrations with the controlled release formulation are similar tothose attained with the first dose of immediate release methylphenidateand from approximately 10 hours post-dose, are higher than thosefollowing the second dose of immediate release methylphenidate.

[0250] The results indicate the potential for a single morning dose ofthis formulation to produce clinical effects that are at leastequivalent to those of two doses of immediate-release methylphenidategiven at breakfast and lunchtime, with a duration of action that mayreduce the need for a third dose of immediate release methylphenidatelater in the day.

EXAMPLE 8 Five-Way Comparison of Single Dose Formulation 2 (Fed andFasted), Single Dose Formulation 3 (Fed and Fasted) and Single DoseRitalin SR (Fasted)

[0251] A five-way blind study was conducted which compared a single doseof Formulation 2, 20 mg, both fed and fasted, a single dose ofFormulation 3, 20 mg, both fed and fasted, and Ritalin SR 20 mg singledose fasted. According to the published literature and anecdotalcomments from physicians, Ritalin SR is used in less than 20% ofmethylphenidate treated patients.

[0252] Twelve healthy male volunteers were given a single dose of either20 mg Formulation 2 or Formulation 3 administered four hours apart underboth fed and fasting conditions (n=12), or slow-release 20 mgmethylphenidate (Ritalin SR) under fasting conditions. “Fed” conditionsindicates the test formulation was given to the subjects after they hadeaten a high-fat breakfast. Following an overnight fast of at least 10.0hours, each of the normal, healthy, non-smoking, male subjects weregiven the following treatments according to Williams design 5 treatmentrandomization scheme.

[0253] Treatment 1: Test Product: methylphenidate controlled-release,Formulation 2, 20 mg capsule, in the morning under fasting conditions.

[0254] Treatment 2: Test Product: methylphenidate controlled-release,Formulation 2, 20 mg capsule, in the morning, under fed conditions.

[0255] Treatment 3: Test Product: methylphenidate controlled-release,Formulation 3, 20 mg capsule, under fasting conditions.

[0256] Treatment 4: Test Product: methylphenidate controlled-release,Formulation 3, 20 mg capsule, under fed conditions.

[0257] Treatment 5: Reference Product: methylphenidate slow-release 20mg tablet Ritalin SR (Novartis) under fasting conditions.

[0258] There was a seven day washout period between the study periods.During each study period, blood samples (1×5 mL each) were taken fromeach subject within one hour prior to dosing and at 0.250, 0.500, 0.750,1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00,10.0, 12.0, 16.0, 24.0 hours post-dose. Plasma was harvested from eachblood sample and stored in a −20 C freezer until assayed for plasmamethylphenidate concentration.

[0259] The data is presented graphically in FIGS. 5-8. FIG. 5 presentsthe mean plasma concentration versus time for Formulation 2 underfasting and fed conditions and Ritalin® under fasting conditions. FIG. 6presents the mean plasma concentration versus time for Formulation 3under fasting and fed conditions and Ritalin® under fasting conditions.FIG. 7 presents the mean plasma concentration versus time forFormulations 2 and 3 under fasting conditions. FIG. 8 presents the meanplasma concentration versus time for Formulations 2 and 3 under fedconditions.

[0260] The complete pharmacokinetic parameters of controlled releasemethylphenidate 20 mg (Formulation 2 and 3) under fed and fastingconditions, and for slow release methylphenidate 20 mg (Ritalin® SR)under fasting conditions are summarized in Tables 22-24 below. TABLE 22Pharmacokinetic Parameters for Formulation 2 Treatment 1, FastingTreatment 2, Fed Parameters Means ± SD CV (%) Mean ± SD CV (%) AUC_(0-t)(pg · h/mL) 48190.73 ± 11668.71 24.21 53452.63 ± 12820.39 23.98AUC_(0-inf) (pg · h/mL) 49787.07 ± 12053.23 24.21 55690.49 ± 12691.5222.79 C_(max) (pg · h/mL)  7498.57 ± 1968.38 26.25  6879.09 ± 1486.5321.61 T_(max) (h)   3.63 ± 0.57 15.70   6.42 ± 1.08 16.89 K_(el) (h⁻¹) 0.2391 ± 0.0428 17.91  0.2321 ± 0.0342 14.75 T_(1/2) (h)   3.00 ± 0.6421.32   3.05 ± 0.48 15.74

[0261] TABLE 23 Pharmacokinetic Parameters for Formulation 3 Treatment3, Fasting Treatment 4, Fed Parameters Means ± SD CV (%) Mean ± SD CV(%) AUC_(0-t) (pg · h/mL) 48057.06 ± 14743.87 30.68 54128.75 ± 14787.9427.32 AUC_(0-inf) (pg · h/mL) 49984.68 ± 14873.03 29.76 56315.66 ±14779.59 26.24 C_(max) (pg · h/mL)  6080.97 ± 2048.60 33.69  6959.07 ±1559.34 22.41 T_(max) (h)   3.46 ± 0.89 25.76   4.42 ± 0.56 12.62 K_(el)(h⁻¹)  0.2009 ± 0.0468 23.32  0.2057 ± 0.0390 18.97 T_(1/2) (h)   3.65 ±0.97 26.52   3.49 ± 0.70 20.01

[0262] TABLE 24 Pharmacokinetic Parameters for Ritalin SR ® ParametersMean ± SD CV (%) AUC_(0-t) (pg · h/mL) 47404.51 ± 12754.66 26.91AUC_(0-inf) (pg · h/mL) 49252.17 ± 12841.52 26.07 C_(max) (pg/mL) 6783.09 ± 1496.65 22.06 T_(max) (h)   3.50 ± 0.43 12.18 K_(el) (h⁻¹) 0.2282 ± 0.0320 14.01 T_(1/2el) (h)   3.10 ± 0.47 15.14

[0263] The results of the ANOVA and Duncan's Multiple Range Testperformed on the ln-transformed C_(max) data show a statisticallysignificant difference between treatments for this parameter. Accordingto Duncan's Multiple Range Test, the C_(max) of treatment 3 wassignificantly different from the C_(max) of treatments 4 and 5. However,Duncan's Multiple Range Test did not detect statistically significantdifferences between treatments for C_(max) when comparing treatment 1vs. treatment 2 or treatment 1 vs treatment 5. The statistical analysesperformed on the data are summarized in Table 25 below: TABLE 25 C_(max)(pg/mL) TRT 1 vs. TRT 3 vs. TRT 1 vs. TRT 3 vs. TRT 2 TRT 4 TRT 5 TRT 5Ratio 103.73% 84.78% 109.25% 87.40% 90% Geometric  98.94% to 78.59% to101.28% to 81.05% to C.I. 115.14% 91.45% 117.85% 94.26%

[0264] The ANOVA and Duncan's Multiple Range Test performed on theln-transformed T_(max) data detected a statistically significantdifference between treatments for this parameter. Duncan's MultipleRange Test detected statistically significant differences betweentreatments 1 and 2, and treatments 3 and 4 for this parameter. Duncan'sMultiple Range Test did not detect statistically significant differencesbetween treatments for To a when comparing treatments 1 vs. 3 ortreatments 3 vs. 5.

[0265] The ANOVA performed on the T_(1/2 el) data detected astatistically significant difference between treatments for thisparameter. Duncan's Multiple Range Test detected no statisticallysignificant differences between treatments 1 and 2, treatments 3 and 4,and treatments 1 and 5 for T_(1/2 el). However, Duncan's Multiple RangeTest detected statistically significant differences between treatments 3and 5 for this parameter.

[0266] The ANOVA performed on the K_(el) data show a statisticallysignificant difference between treatments for this parameter.Statistically significant differences were not detected by Duncan'sMultiple Range Test, between treatments for K_(el) when comparingtreatments 1 and 2, treatments 3 and 4, or treatments 1 and 5. However,Duncan's Multiple Range Test detected statistically significantdifferences between treatments 3 and 5 for this parameter.

[0267] The ANOVA and Duncan's Multiple Range Test performed on theln-transformed AUC_(0-t) data show a statistically significantdifference between treatments for this parameter. According to Duncan'sMultiple Range Test, the AUC_(0-t) of treatments 1 and 3 wassignificantly different from the AUC_(0-t) of treatments 2 and 4respectively. However, Duncan's Multiple Range Test did not detectstatistically significant differences between treatments for AUC_(0-t)when comparing treatment 1 vs treatment 5, or treatment 3 vs treatment5. The statistical analyses performed on the data are summarized belowin Table 26: TABLE 26 AUC_(0-t) (pg · h/mL) Treatment TreatmentTreatment Treatment 1 vs. 3 vs. 1 vs. 3 vs. Treatment 2 Treatment 4Treatment 5 Treatment 5 Ratio 89.21% 88.23% 101.82% 100.63% 90%Geometric 84.03% to 83.10% to  95.91% to  94.81% to C.I. 94.71% 93.67%108.10% 106.81%

[0268] The ANOVA and Duncan's Multiple Range Test performed on theln-transformed AUC_(0-inf) data show a statistically significantdifference between treatments for this parameter. According to Duncan'sMultiple Range Test, the AUC_(0-inf) of treatments 1 and 3 wassignificantly different from the AUC_(0-inf) of treatments 2 and 4respectively. However, Duncan's Multiple Range Test did not detectstatistically significant differences between treatments for AUC_(0-inf)when comparing treatment 1 vs treatment 3, or treatment 3 vs treatment5. The statistical analyses performed on the data are summarized belowin Table 27: TABLE 27 AUC_(0-int) (pg · h/mL) TRT 1 vs. TRT 3 vs. TRT 1vs. TRT 3 vs. TRT 2 TRT 4 TRT 5 TRT 5 Ratio 88.33% 88.14% 101.14%100.82% 90% Geometric 83.50% to 83.32% to  95.61% to  95.33% to C.I.93.44% 93.24% 106.99% 106.63%

[0269] Treatment 1 (Formulation 2, Fasting) vs. Treatment 2 (Formulation2, Fed)

[0270] The ANOVAs detected statistically significant differences betweenfed and fasting conditions, treatments 1 and 2, for the ln-transformedAUC_(0-t), AUC_(0-inf) and C_(max) and untransformed T_(max), T_(1/2el)and K_(el). Duncan's Multiple Range Test detected statisticallysignificant differences between treatments 1 and 2 for ln-transformedAUC_(0-t) and AUC_(0-inf) and untransformed T_(max). However, Duncan'sMultiple Range Test detected no statistically significant differencesbetween treatments for ln-transformed C_(max) and untransformedT_(1/2el) and K_(el). All formulation ratios, as well as 90% geometricconfidence intervals of the relative mean AUC_(0-t), AUC_(0-inf) andC_(max) were found to be within the 80% to 125%, as is shown in Table 28below. Thus, it appears that food increases the extent of absorption ofmethylphenidate for Formulation 2. However, this food effect was lessthan 20% on average. TABLE 28 Formulation 2, Fed versus FastingAUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 112.09% 113.21% 93.69% 90% 105.58%to 107.03% to 86.85% to 101.07% Geometric C.I.² 119.00% 119.76%

[0271] Treatment 3 (Formulation 3, Fasting) vs. Treatment 4 (Formulation3, Fed)

[0272] The ANOVAs detected statistically significant differences betweentreatments for ln-transformed AUC_(0-inf) and C_(max) and untransformedT_(max), T_(1/2el) and K_(el). Duncan's Multiple Range Test detectedstatistically significant differences between treatments 3 and 4 forln-transformed AUC_(0-t), AUC_(0-inf) and C_(max) and untransformedT_(max). However, Duncan's Multiple Range Test detected no statisticallysignificant differences between treatments for untransformed T_(1/2el)and K_(el). With the exception of lower 90% geometric confidenceinterval for C_(max), all formulation ratios, as well as 90% geometricconfidence intervals of the relative mean AUC_(0-t), AUC_(0-inf) andC_(max) were found to be within the 80% to 125%, as is shown in Table 29below. Thus, it appears that food increases the extent of absorption ofmethylphenidate for Formulation 3. However, this food effect was lessthan 20% on average. TABLE 29 Formulation 3, Fed versus FastingAUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 113.35% 113.45% 117.96% 90% 106.76%to 107.25% to 120.01% 109.35% to Geometric 120.33% 127.25% C.I.²

[0273] Treatment 1 (Formulation 2, Fasting) vs. Treatment 5 (RitalinSR®, Fasting)

[0274] The ANOVAs detected statistically significant differences betweentreatments for ln-transformed AUC_(0-t), AUC_(0-inf) and C_(max) anduntransformed T_(max)) T_(1/2el) and K_(el). Duncan's Multiple RangeTest detected no statistically significant differences betweentreatments 1 and 5 for all parameters. All formulation ratios, as wellas 90% geometric confidence intervals of the relative mean AUC_(0-t),AUC_(0-inf) and C_(max) of the test to reference product were found tobe within the 80% to 125%, as shown in Table 30 below. Thus, Formulation2 is bioequivalent to the reference product Ritalin SR® under fastingconditions TABLE 30 Formulation 2 (Fasting) versus Ritalin SR (Fasting)AUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 101.82% 101.14% 106.99% 90%  95.91%to  95.61% to 101.28 to Geometric C.I.² 108.10% 106.99% 117.85%

[0275] Treatment 3 (Formulation 3, Fasting) vs. Treatment 5 (RitalinSR®, Fasting)

[0276] The ANOVAs detected statistically significant differences betweentreatments for ln-transformed AUC_(0-t), AUC_(0-inf) and C_(max) anduntransformed T_(max), T_(1/2el) and K_(el). Duncan's Multiple RangeTest detected statistically significant differences between treatments 3and 5 for ln-transformed Can and untransformed T_(1/2el) and K_(el).However, Duncan's Multiple Range Test detected no statisticallysignificant differences between treatments for ln-transformed AUC_(0-t)and AUC_(0-inf) and untransformed T_(max). All formulation ratios, aswell as 90% geometric confidence intervals of the relative meanAUC_(0-t), AUC_(0-inf) and C_(max) of the test to reference product werefound to be within the 80% to 125%, as shown in Table 31 below. Thus,Formulation 3 is bioequivalent to the reference product Ritalin SR®under fasting conditions. TABLE 31 Formulation 3 (Fasting) versusRitalin SR (Fasting) AUC_(0-t) AUC_(0-inf) C_(max) Ratio¹ 101.63%100.82% 87.40% 90%  94.81% to  95.33% to 81.05 to Geometric C.I.²106.81% 106.63% 94.26%

CONCLUSIONS

[0277] The bioavailability of Formulation 2 relative to Ritalin SR® isacceptable under fasted conditions (Relative AUC_(inf) 101%—Fedconditions not tested).

[0278] The bioavailability of Ritalin SR® under fasted conditions issimilar to that of Ritalin® IR, as discussed in Example 7 (AUC_(inf)29.2 vs. 46.5 ng.h/mL, respectively). Literature data which indicatesthat Ritalin® IR and SR are absorbed at equivalent rates suggests thatcomparisons between the studies presented in Examples 7 and 8 arereasonable.

[0279] Bioavailability of Formulations 1 and 2 are similar under fastedand fed conditions (fasted: 49.8 vs. 51.2 ng.h/mL; fed: 55.7 vs. 57.9ng.h/mL).

[0280] From the mean curves of Formulation 2 and Ritalin SR®, theinitial rate of rise of plasma MPH concentration is slightly faster forFormulation 2 compared to Ritalin SR®. Under fed conditions, the rate ofrise of plasma MPH with Formulation 2 decreased and T_(max) was delayedin comparison to both Formulation 2 fasted and Ritalin SR® fasted.

[0281] Bioavailability of Formulation 3 relative to Ritalin SR® isacceptable under fasted conditions (Relative AUC_(inf) 100.8%—fedconditions not tested).

[0282] Bioavailability of Formulations 1 and 3 are similar under fastedand fed conditions (fasted: 50.0 versus 51.2 ng/mL; fed: 56.3 versus57.9 ng-h/mL). Note also that Formulations 2 and 3 have almost identicalAUC values.

[0283] From the mean curves for Formulation 3 and Ritalin SR®, theinitial rate of rise of plasma MPH concentrations is slightly faster forFormulation 3 compared to Ritalin SR®.

[0284] In contrast to Formulation 2, the effect of food on the initialrate of concentration rise is minimal. Since Formulation 3 does notcontain an enteric coat, this suggests that food slows the initialrelease from the IR component of formulations that contain an entericcoat, both when the enteric coat is part of the same bead (underneaththe IR coat in the case of Formulation 1) and when it is in a separatebead (as for Formulation 2).

[0285] Also in contrast to Formulation 2, the T_(max) of the mean curveof Formulation 3 occurs at a similar time to that of Ritalin SR® underfed and fasted conditions. For Formulation 2 (and Formulation 1) theT_(max) of the second absorption phase under fed conditions issubstantially delayed relative to Ritalin SR®.

CONCLUSIONS—EXAMPLES 7 AND 8

[0286] 1. Formulation 1 has both a fast initial rate of rise, at leastunder fasted conditions and a prolonged duration. The transformationfrom a prolonged plateau profile under fasted conditions to a biphasicprofile under fed conditions, is as predicted. Since these conditionsrepresent the extremes of “food stress”, one might predict thatadministration in association with normal meals and times would providean intermediate profile. It is also possible that gastric emptying inchildren on a normal meal schedule will be faster than in adults fed ahigh fat meal—this will tend to make the second absorption phase occurearlier and produce lower concentrations from 12 hours onwards.Formulation 1 therefore meets the dual objectives of rapid onset andprolonged duration.

[0287] 2. Formulation 2 is also very similar to Ritalin SR® under fastedconditions but shows a delayed peak under fed conditions such thatplasma MPH concentrations are higher than Ritalin SR® (fasted) from 6hours post dose onwards. The controlled release component in Formulation2 is faster releasing than the one in Formulation 1 and plasma MPHconcentrations are lower for Formulation 2 from about 10 hours postdose.

[0288] 3. Overall, Formulation 3 (non-enteric coated) has a profile verysimilar to Ritalin SR® under both fed and fasted conditions. The IRcomponent of Formulation 3 provides some increase in initial absorptionrate relative to Ritalin SR® under fasted conditions. Sinceconcentrations later in the day are similar for the two formulations,this confirms the concept that a fast initial rise and higherconcentrations later in the day are not possible at the same dose,unless a delay is introduced into the release of a component of thetotal dose.

EXAMPLE 9

[0289] Example 9 is directed to another embodiment of the inventionwherein a formulation is prepared which provides both rapid initialonset of effect and prolonged duration, and which provides a peakconcentration which is not lower than Ritalin IR, while providing aprolonged duration which is not too long and which does not oauseinsomnia at night. An ideal target plasma drug concentration profile isshown in FIG. 9, which is a plot of Ritalin IR versus Ritalin SR versusFormulation 1 (described above in Example 7) versus the “target”formulation of Example 9.

[0290] Assuming first order elimination of methylphenidate in human, thefirst order elimination rate constant was estimated from the linearterminal slope of plasma methylphenidate concentration curve (as plottedin log-linear paper) following oral administration of Ritalin IR. Theabsorption profile of Formulation 1 described above can be obtainedfollowing deconvolution calculation of the plasma drug concentrationprofile of the same using the Wagner-Nelsen Method (“Fundamentals ofClinical Pharmacokinetics” by John G. Wagner, Drug IntelligencePublications, Inc. 1975, page 174). The in-vitro drug dissolutionprofile correlates well with the in-vivo absorption profile, as shown inFIG. 10. This correlation indicates that the in-vitro dissolution methodcan be used to predict in-vivo drug absorption.

[0291] To obtain a target absorption/dissolution profile, assuming firstorder elimination of methylphenidate in human, the first orderelimination rate constant was estimated from the linear terminal slopeof the plasma methylphenidate concentration curve (as plotted inlog-linear paper) following oral administration of Ritalin IR, via theWagner-Nelsen Method. The target absorption profile is depicted in FIG.11. Based on the established in-vitro/in-vivo correlation as shown inFIG. 10, assuming a similar drug release mechanism is utilized, thisin-vivo absorption curve can be taken as the target dissolution profile.

EXAMPLE 10

[0292] In Example 10, a methylphenidate formulation in accordance withthe present invention is prepared utilizing a melt extrusion granulation(MEG) technique. The ingredients are set forth in the following Table32. TABLE 32 Ingredient mg/tablet Methylphenidate HCl 15.0 Eudragit RSPO25.0 Stearyl Alcohol 25.0 Eudragit L 100-55 5.0 Avicel PH 102 30.0 Talc2.0 Magnesium Stearate 1.0 103

[0293] Method of Manufacture:

[0294] The Methylphenidate HCl, Eudragit RSPO, Stearyl Alcohol, EudragitL100-55 and Avicel are blended. The powder blend is fed into a turnscrew melt extruder. The heating zones are set to 80° C. and screw speedat 30 rpm, and the powder is fed through the extruder at the elevatedtemperature, and is extruded as warm strands through a die plate withholes of 1 mm. The extruded strands are cooled on the conveyor belt. Thecooled strands are then broken into smaller pieces. The broken strandsare then milled into a granulation using a Fitzmill. The granulation isthen blended with the talc and magnesium stearate and compressed intotablets using a tabletting machine.

[0295] The expected dissolution of both these tablets, using USP basketapparatus 1 with a paddle speed of 100 rpm in 500 ml SGF at pH 1.2 fortwo hours followed by 500 ml phosphate buffer at pH 5.8 is set forth inTable 33: TABLE 33 In-Vitro Dissolution Target Hour % Dissolved %Dissolved 1 31 31 3 61 58 8 89 98

EXAMPLE 11

[0296] In Example 11, a methylphenidate formulation in accordance withthe present invention is prepared utilizing the melt extrusiongranulation (MEG) technique as set forth in Example 10. The ingredientsare set forth in Table 34. TABLE 34 Ingredient mg/tablet MethylphenidateHCl 15.0 Eudragit RSPO 25.0 Stearyl Alcohol 15.0 Eudragit L 100-55 5.0Avicel PH 102 30.0 Polyethylene glycol 8000 10.0 Talc 2.0 MagnesiumStearate 1.0 103

[0297] The expected dissolution of both these tablets, using USP basketapparatus 1 with a paddle speed of 100 rpm in 500 ml SGF at pH 1.2 fortwo hours followed by 500 ml phosphate buffer at pH 5.8 is set forth inTable 35: TABLE 35 Target Hour % Dissolved % Dissolved 1 30 31 3 59 58 890 98

EXAMPLE 12

[0298] In Example 12, another method of producing controlled releaseMethylphenidate HCl tablets in accordance with the present invention isutilized, via a direct compression technique. The ingredients of Example12 are set forth in Table 36 below: TABLE 36 Ingredient mg/tabletMethylphenidate HCl 15.0 Lactose DT 15.0 Methocel 67.0 Talc 2.0Magnesium Stearate 1.0 100

[0299] Method of Manufacture:

[0300] The ingredients are blended. The blended material is compressedinto tablets. When these tablets were tested for dissolution using thesame methodology noted above, the results were as set forth in Table 37below: TABLE 37 Target Hour % Dissolved % Dissolved 1 33 31 3 71 58 8 9898

EXAMPLE 13

[0301] In Example 13, the method of producing controlled releaseMethylphenidate HCl tablets in accordance with Example 12 is utilized,via a direct compression technique to produce another formulation. Theingredients of Example 13 are set forth in Table 38 below: TABLE 38Ingredient mg/tablet Methylphenidate HCl 15.0 Lactose DT 15.0 Eudragit L100-55 15.0 Methocel 52.0 Talc 2.0 Magnesium Stearate 1.0 100

[0302] When the tablets were tested for dissolution using the samemethodology noted above, the results were as set forth in Table 39below: TABLE 39 Target Hour % Dissolved % Dissolved 1 37 31 3 67 58 8 8798

[0303] The examples provided above are not meant to be exclusive. Manyother variations of the present invention would be obvious to thoseskilled in the art, and are contemplated to be within the scope of theappended claims.

What is claimed is:
 1. An oral dosage form comprising an effectiveamount of methylphenidate or a pharmaceutically acceptable salt thereofand at least one release modifying material which causes the formulationto provide a time to maximum plasma concentration at about 0.5 to about4 hours after oral administration, a peak plasma concentration fromabout 3 ng/ml to about 6.5 ng/ml per 20 mg dose of methylphenidatecontained in the oral dosage form, wherein the peak plasma concentrationis from about 1.0 to about 2.0 times the plasma concentration ofmethylphenidate provided by the formulation at about 9 hours after oraladministration, and wherein the duration of effect provided by themethylphenidate contained in the formulation falls below effectiveplasma concentrations at about 8 to about 12 hours after oraladministration.
 2. The oral dosage form of claim 1, wherein the oraldosage form provides a time to maximum plasma concentration at about0.5° to about 2 hours after oral administration.
 3. The oral dosage formof claim 2, wherein the peak plasma concentration is from about 1.0 toabout 1.7 times the plasma concentration of methylphenidate provided bythe formulation at about 9 hours after oral administration.
 4. The oraldosage form of claim 3, wherein the duration of effect provided by themethylphenidate contained in the oral dosage form falls below effectiveplasma concentrations at about 8 to about 10 hours after oraladministration.
 5. The oral dosage form of claim 1, which provides a“square wave” plasma profile as depicted by Formulation
 1. 6. An oraldosage form of claim 1, which provides an in-vitro dissolution asfollows: Time % Methylphenidate (hours) HCl dissolved 0.25  0-45% 1 5-50% 4 40-90% 8 NLT 60% 12 NLT 80%


7. An oral dosage form of claim 1, which provides an in-vitrodissolution as follows: Time % Methylphenidate (hours) HCl dissolved0.25  0-45% 1 10-50% 4 30-80% 8 NLT 65% 12 NLT 80%


8. An oral dosage form comprising an effective amount of methylphenidateor a pharmaceutically acceptable salt thereof and at least one releasemodifying material which causes the formulation to provide an in-vitrodissolution of the drug of from about 0 to about 45% released after 0.25hour; from about 10 to about 50% released after about 1 hour; from about30 to about 80% drug released after about 4 hours; not less than about65% drug released after 8 hours; and not less than about 80% of the drugreleased after about 12 hours; the oral dosage form when orallyadministered to a human patient further providing a time to maximumplasma concentration at about 0.5 to about 2 hours after oraladministration, and a duration of effect which lasts from about 8 toabout 10 hours after oral administration, wherein the plasmaconcentration of the drug rapidly falls at about 8 to about 10 hoursafter oral administration to a level which is below the minimumeffective plasma concentration.
 9. The oral dosage form of claim 8,which when orally administered provides a peak plasma concentration fromabout 4 ng/ml to about 6.5 ng/ml per 20 mg dose of methylphenidatecontained in the oral dosage form.
 10. The oral dosage form of claim 8,which when orally administered provides a peak plasma concentration fromabout 5 ng/ml to about 6.5 ng/ml per 20 mg dose of methylphenidatecontained in the oral dosage form.
 11. The oral dosage form of claim 8,wherein the peak plasma concentration is from about 1.0 to about 2.0times the plasma concentration of methylphenidate provided by theformulation at about 9 hours after oral administration.
 12. The oraldosage form of claim 8, wherein the peak plasma concentration is fromabout 1.0 to about 1.7 times the plasma concentration of methylphenidateprovided by the formulation at about 9 hours after oral administration.